Other entities represented in this entry:
ORPHA: 758; DO: 2738;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.11 | Pseudoxanthoma elasticum, forme fruste | 177850 | Autosomal dominant | 3 | ABCC6 | 603234 |
A number sign (#) is used with this entry because individuals heterozygous for mutation in the ABCC6 gene (603234) in the overwhelming majority of cases express limited manifestations of the pseudoxanthoma elasticum phenotype. In rare cases heterozygosity for mutations in the ABCC6 gene appears to result in expression of the full PXE phenotype in 2 generations (see 603234.0018).
A digenic form of PXE resulting from an ABCC6 mutation (603234.0001) and a GGCX mutation (137167.0012) has been reported.
For a phenotypic description of PXE, see 264800.
Hausser and Anton-Lamprecht (1991) described a family in which the mother and grandmother died because of major vascular complications of PXE. Three adolescent sibs showed no clinical manifestations of PXE. However, ultrastructural investigation of overtly normal skin in sites of predilection gave a positive diagnosis. Dermal connective tissue showed a specific aberrant pattern; elastin (130160) of elastic fibers regularly contained small foci of calcification resembling those in perilesional skin of the mother and other PXE patients; in collagen bundles adjacent to altered elastic fibers, collagen fibrils occurred with thickened diameters and flower-like contours.
Van Soest et al. (1997) reported a family from a genetically isolated population in the Netherlands with autosomal recessive PXE in which vascular symptoms appeared in 40 to 50% of the heterozygotes.
Bacchelli et al. (1999) and Sherer et al. (2001) presented evidence that heterozygous mutant family members of affected individuals present limited manifestations of PXE.
Bergen et al. (2000), Le Saux et al. (2000), and Ringpfeil et al. (2000) identified missense, nonsense, and splice site mutations, as well as deletions and insertions, in the ABCC6 gene (603234) accounting for pseudoxanthoma elasticum (264800). Mutations appeared to represent autosomal recessive (Le Saux et al., 2000) and autosomal dominant (Bergen et al., 2000) modes of inheritance, and sporadic cases. The R114X mutation (603234.0001) was found in families segregating autosomal dominant PXE and in families segregating autosomal recessive PXE.
Plomp et al. (2004) described a family in which criteria for 'definite' PXE were met in 2 generations and in which an arg1459-to-cys substitution (R1459C) in the ABCC protein was detected on 1 allele only (603234.0018). They stated that the R1459C mutation might be one that could cause PXE in the heterozygous state. In their review of families with putative autosomal dominant PXE, including this family and 2 others examined by them, the authors noted that they did not find a single family with definite PXE in 3 or more generations.
Bergen (2006) stated that the family with the apparently heterozygous R1459C mutation studied by Plomp et al. (2004) remained 'an interesting puzzle and is perhaps the always existing 'exception to the rule'.'
Miksch et al. (2005) performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. The resultant data indicated that the inheritance of PXE is exclusively autosomal recessive, and that all mutations in the ABCC6 gene associated with PXE appear to lead to loss of function of the protein. The authors suggested that clinical carriers of the trait with a haplotypic heterozygous allelic status for one of the familial disease alleles may express a forme fruste of the disorder that can be characterized, in part, by category II diagnostic criteria (Neldner and Struk, 2002) according to the consensus conference (Lebwohl et al., 1994). Such carriers may have positive skin biopsy of nonlesional skin and/or show mottled hyperpigmentation or angioid streaks, but will not exhibit the long-term manifestations and complications of the disorder that are the consequences of the loss of function of both ABCC6 alleles. Miksch et al. (2005) stated that in the families examined by them, none of the heterozygotes for a large deletion showed any apparent clinical signs of PXE according to category I diagnostic criteria.
PXE, Forme Fruste, Digenic, ABCC6/GGCX
In a woman and her sister with biopsy-confirmed PXE, Li et al. (2009) identified compound heterozygosity for a mutation in the ABCC6 gene (R1141X; 603234.0001) mutation and a mutation in the GGCX gene (V255M; 137167.0012). Neither had evidence of a coagulopathy, but skin biopsies showed undercarboxylated matrix gla proteins (MGP; 154870) in the areas of abnormal mineralization. Since R1141X in the heterozygous state is usually not associated with clinical features, the findings suggested that women had digenic inheritance of PXE. In contrast, 2 other family members who were compound heterozygous for R1141X and another mutation in the GGCX gene (S300F; 137167.0013) had no signs of either disorder on clinical exam but refused to participate in further clinical testing. Plasma levels of total undercarboxylated MGP in the 2 clinically unaffected individuals were at the lower end of normal. Although the reasons for the lack of clinical findings in these latter individuals remained unclear, Li et al. (2009) concluded that undercarboxylation of MGP plays a critical role in aberrant mineralization of tissues in PXE.
Wise (1966) stated that about a quarter of all families with 2 or more cases of PXE have cases in successive generations. He noted that no quantitative or qualitative difference between the cases could be discerned in families with successive generations affected (autosomal dominant) and families with unaffected but consanguineous parents (autosomal recessive).
In a series of 100 personally studied cases, Neldner (1988) found no instance of 3-generation involvement. Indeed, only 3 patients of the 100 were considered to have autosomal dominant inheritance: a mother-daughter pair and a third patient whose father had biopsy-proven PXE but was not a member of the study. In addition, there were 3 families with 3 affected sibs each and 4 families with 2 affected sibs. The 100 patients came from 88 separate kindreds. Three of the patients from single-patient sibships had cousins with PXE.
Struk et al. (1997) stated that an autosomal dominant pattern of transmission of PXE occurs in approximately 10% of affected families.
Bacchelli, B., Quaglino, D., Gheduzzi, D., Taparelli, F., Boraldi, F., F., Trolli, B., Le Saux, O., Boyd, C. D., Ronchetti, I. P. Identification of heterozygote carriers in families with a recessive form of pseudoxanthoma elasticum (PXE). Mod. Path. 12: 1112-1123, 1999. [PubMed: 10619263]
Bergen, A. A. B. Pseudoxanthoma elasticum: the end of the autosomal dominant segregation myth. (Commentary) J. Invest. Derm. 126: 704-705, 2006. [PubMed: 16541094] [Full Text: https://doi.org/10.1038/sj.jid.5700129]
Bergen, A. A. B., Plomp, A. S., Schuurman, E. J., Terry, S., Breuning, M., Dauwerse, H., Swart, J., Kool, M., van Soest, S., Baas, F., ten Brink, J. B., de Jong, P. T. V. M. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nature Genet. 25: 228-231, 2000. [PubMed: 10835643] [Full Text: https://doi.org/10.1038/76109]
Hausser, I., Anton-Lamprecht, I. Early preclinical diagnosis of dominant pseudoxanthoma elasticum by specific ultrastructural changes of dermal elastic and collagen tissue in a family at risk. Hum. Genet. 87: 693-700, 1991. [PubMed: 1937472] [Full Text: https://doi.org/10.1007/BF00201728]
Lebwohl, M., Neldner, K., Pope, F. M., De Paepe, A., Christiano, A. M., Boyd, C. D., Uitto, J., McKusick, V. A. Classification of pseudoxanthoma elasticum: report of a consensus conference. J. Am. Acad. Derm. 30: 103-107, 1994. [PubMed: 8277008] [Full Text: https://doi.org/10.1016/s0190-9622(08)81894-4]
Le Saux, O., Urban, Z., Tschuch, C., Csiszar, K., Bacchelli, B., Quaglino, D., Pasquali-Ronchetti, I., Pope, F. M., Richards, A., Terry, S., Bercovitch, L., de Paepe, A., Boyd, C. D. Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nature Genet. 25: 223-227, 2000. [PubMed: 10835642] [Full Text: https://doi.org/10.1038/76102]
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]
Miksch, S., Lumsden, A., Guenther, U. P., Foernzler, D., Christen-Zach, S., Daugherty, C., Ramesar, R. S., Lebwohl, M., Hohl, D., Neldner, K. H., Lindpaintner, K., Richards, R. I., Struk, B. Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. Hum. Mutat. 26: 235-248, 2005. [PubMed: 16086317] [Full Text: https://doi.org/10.1002/humu.20206]
Neldner, K., Struk, B. Pseudoxanthoma elasticum.In: Royce, P. M.; Steinmann, B. (eds.) : Connective tissue and its heritable disorders: molecular, genetic, and medical aspects. (2nd ed.) New York: Wiley-Liss (2nd ed.) 2002. Pp. 561-583.
Neldner, K. H. Pseudoxanthoma elasticum. Clin. Derm. 6(1): 83-92, 1988.
Plomp, A. S., Hu, X., de Jong, P. T. V. M., Bergen, A. A. B. Does autosomal dominant pseudoxanthoma elasticum exist? Am. J. Med. Genet. 126A: 403-412, 2004. [PubMed: 15098239] [Full Text: https://doi.org/10.1002/ajmg.a.20632]
Ringpfeil, F., Lebwohl, M.G., Christiano, A. M., Uitto, J. Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc. Nat. Acad. Sci. 97: 6001-6006, 2000. [PubMed: 10811882] [Full Text: https://doi.org/10.1073/pnas.100041297]
Sherer, D. W., Bercovitch, L., Lebwohl, M. Pseudoxanthoma elasticum: significance of limited phenotypic expression in parents of affected offspring. J. Am. Acad. Derm. 44: 534-537, 2001. [PubMed: 11209132] [Full Text: https://doi.org/10.1067/mjd.2001.112401]
Struk, B., Neldner, K. H., Rao, V. S., St Jean, P., Lindpaintner, K. Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1. Hum. Molec. Genet. 6: 1823-1828, 1997. [PubMed: 9302259] [Full Text: https://doi.org/10.1093/hmg/6.11.1823]
van Soest, S., Swart, J., Tijmes, N., Sandkuijl, L. A., Rommers, J., Bergen, A. A. B. A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1. Genome Res. 7: 830-834, 1997. [PubMed: 9267806] [Full Text: https://doi.org/10.1101/gr.7.8.830]
Wise, D. Hereditary disorders of connective tissues.In: Gottron, H.; Schnyder, U. : Vererbung von Hautkrankheiten. Berlin: Springer-Verlag (pub.) 1966. P. 471.