Alternative titles; symbols
ORPHA: 91135;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p11.2 | Pseudoxanthoma elasticum-like disorder with multiple coagulation factor deficiency | 610842 | 3 | GGCX | 137167 |
A number sign (#) is used with this entry because of evidence that the PXE-like disorder with multiple coagulation factor deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding gamma-glutamyl carboxylase (GGCX; 137167) on chromosome 2p11.
Vanakker et al. (2007) described 6 patients with a disorder sharing features of pseudoxanthoma elasticum (PXE; 264800) and cutis laxa (see 219100) and associated with multiple coagulation factor deficiency (see 277450). Clinical overlap of PXE was obvious from the skin manifestations of yellowish papules or leathery plaques, with dot-like depressions at presentation, angioid streaks and/or ocular peau d'orange, and fragmentation and calcification of elastic fibers in the dermis. Important phenotypic differences from PXE included much more severe skin laxity with involvement of the trunk and limbs with thick, leathery skin folds rather than confinement to flexural areas, and no decrease in visual acuity. By light microscopy, the changes in the reticular dermis were identical to those typical of PXE: elastic fibers were polymorphous, fragmented, and mineralized, as shown by von Kossa stain. On the ultrastructural level, however, elastic fibers had a more fragmented and mottled appearance than that observed typically in PXE.
A PXE-like disorder with multiple coagulation factor deficiency had been described in case reports by MacMillan and Vickers (1971), Rongioletti et al. (1989), and Le Corvaisier-Pieto et al. (1996). The 2 patients reported by MacMillan and Vickers (1971) were identical twin sisters, aged 24. Another sister, aged 9, had the same coagulation defect as the twins but her skin at the time of the report was clinically normal.
Vanakker et al. (2007) reviewed the findings in 4 previously reported cases in comparison with their 6 molecularly characterized cases. In the patients reported by Vanakker et al. (2007), funduscopy revealed only limited angioid streaks and/or peau d'orange, and visual acuity was normal in all patients. Cardiovascular investigations showed subclinical atherosclerotic plaques in the lower limbs in 2 patients and vascular occlusion with intermittent claudication in 1 patient. In 1 patient, 2 cerebral aneurysms were discovered at age 36 and 46 years and successfully treated. Clinical manifestations of the coagulation defects were present in only 2 patients: 1 suffered 3 meningeal hemorrhages over a period of 20 years, a postpartum hemorrhage after delivery of her only child, and 1 episode of unexplained hematemesis. Another patient had a history of epistaxis, spontaneous gingival bleeding, and severe vaginal hemorrhages.
In 6 patients with a PXE-like phenotype with multiple vitamin K-dependent clotting factors, Vanakker et al. (2007) found mutations in the GGCX gene (137167), which is also implicated in a form of multiple vitamin K-dependent coagulation factor deficiency (277450) and which encodes an enzyme important for gamma-carboxylation of Gla proteins. The authors found homozygosity for a missense mutation in 1 case (137167.0007), and compound heterozygosity in 3 other cases (e.g., 137167.0005). In 2 other cases, only 1 mutant allele was characterized (137167.0010, 137167.0011). Vanakker et al. (2007) concluded that PXE-like disorder with multiple coagulation factor deficiency is inherited as a recessive. Molecular analyses of the candidate genes ABCC6 (603234), mutations in which are responsible for PXE, and VKORC1 (608547), mutations in which cause another form of deficiency of multiple vitamin K-dependent coagulation factors (607473), failed to find mutations.
In 2 sisters with PXE-like disorder and multiple coagulation factor deficiency, Li et al. (2009) identified compound heterozygosity for the V255M (137167.0012) and S300F (137167.0013) mutations in the GGCX gene. Skin biopsies from the patients showed undercarboxylated matrix gla proteins (MGP; 154870) in the areas of abnormal mineralization.
Vanakker et al. (2007) noted that the GGCX mutations they found resulting in the PXE-like disorder with multiple coagulation factor deficiency occurred in exons 8, 10, or 12. Mutations in these exons had not been described in patients with the hereditary coagulation disorder without the cutaneous phenotype. Vanakker et al. (2007) hypothesized that these exons are of critical importance in domains that are essential not only in the activating role of the GGCX enzyme in the coagulation cascade, but also for the activation of other Gla proteins such as, for example, MGP or osteocalcin (112260). The latter are known inhibitors of calcification. Hence, a decreased or absent activation of such proteins could explain the calcification and subsequent fragmentation of the elastic fibers. The severity of the skin lesions might be due to the additive effect of decreased or absent activity of multiple calcification inhibitors.
Le Corvaisier-Pieto, C., Joly, P., Thomine, E., Lair, G., Lauret, P. Generalized pseudoxanthoma elasticum combined with vitamin K dependent clotting factors deficiency. Ann. Derm. Venereol. 123: 555-558, 1996. [PubMed: 9615107]
Li, Q., Grange, D. K., Armstrong, N. L., Whelan, A. J., Hurley, M. Y., Rishavy, M. A., Hallgren, K. W., Berkner, K. L., Schurgers, L. J., Jiang, Q., Uitto, J. Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes. J. Invest. Derm. 129: 553-563, 2009. [PubMed: 18800149] [Full Text: https://doi.org/10.1038/jid.2008.271]
MacMillan, D. C., Vickers, H. R. Pseudoxanthoma elasticum and a coagulation defect. Brit. J. Derm. 84: 182 only, 1971. [PubMed: 5548470]
Rongioletti, F., Bertamino, R., Rebora, A. Generalized pseudoxanthoma elasticum with deficiency of vitamin K-dependent clotting factors. J. Am. Acad. Derm. 21: 1150-1152, 1989. [PubMed: 2808851] [Full Text: https://doi.org/10.1016/s0190-9622(89)70320-0]
Vanakker, O. M., Martin, L., Gheduzzi, D., Leroy, B. P., Loeys, B. L., Guerci, V. I., Matthys, D., Terry, S. F., Coucke, P. J., Pasquali-Ronchetti, I., De Paepe, A. Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity. J. Invest. Derm. 127: 581-587, 2007. [PubMed: 17110937] [Full Text: https://doi.org/10.1038/sj.jid.5700610]