Early preclinical diagnosis of dominant pseudoxanthoma elasticum by specific ultrastructural changes of dermal elastic and collagen tissue in a family at risk

Abstract

The preferred description for the Grönblad-Strandberg syndrome, pseudoxanthoma elasticum (PXE), refers only to the cutaneous aspect of the disease, although the skin is the least severely involved organ. The potential catastrophic manifestation of this heterogeneous heritable disorder is described in a dominant pedigree where mother and grandmother died because of major vascular problems. The family requested predictive testing of the three children. Diagnosis of PXE is usually performed by morphological examination of skin lesions, which reveal incrustations formed by inorganic ions (mainly calcium) and various organic (degraded?) materials in the elastin moiety of the elastic fibers. The ubiquitous elastic fibers in other organs and arteries may be similarly involved. Moreover, there is co-involvement of collagen fibrils at the electron microscopical level. The three adolescent siblings did not show any clinical PXE symptoms. However, ultrastructural investigation of overtly normal skin in predilection sites gave a positive diagnosis for this dominant PXE type. Dermal connective tissue showed a specific aberrant pattern: elastin 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; ground substance material was increased. The possible pathogenetic mechanism and problems posed by predictive testing of adult-onset diseases are discussed.

Pseudoxanthoma elasticum: Wide phenotypic variation in homozygotes and no signs in heterozygotes for the c.3775delT mutation in ABCC6

“…14 Histopathologic abnormalities were found in skin biopsies from some probably heterozygous first-degree relatives of patients with PXE. 13,34,35 Most frequent abnormalities were increase and fragmentation of elastin, which were found less frequently in controls, but which we consider aspecific for PXE. In some biopsies, calcification of elastic fibers was present, but no clumping was mentioned.…”

“…In some biopsies, calcification of elastic fibers was present, but no clumping was mentioned. 13,34 Christen-Zäch et al did not find any skin or eye signs of PXE in 67 heterozygous persons. From four of them (6%) skin biopsies were examined, which were also normal.…”

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum

“…However, there are a number of reports in the literature of families in which PXE potentially segregates in an ad fashion. 6,7 These segregation patterns may result from pseudodominant inheritance, as a result of parental consanguinity, or (mild) manifestation of the disease in heterozygotes. [36][37][38][39] On the other hand, the presence of rare ABCC6/MRP6 mutations resulting in a true ad disease and inheritance pattern cannot be ruled out completely.…”

“…6 In a small number of families, autosomal dominant (ad) inheritance has been reported. 6,7 We and others previously localized the PXE gene to chromosome 16p13.1, 8,9 and found that mutations in the ABCC6/MRP6 (MRP6) gene are associated with all genetic forms of PXE. [10][11][12] The ABCC6/MRP6 gene is a member of the ATP-binding cassette (ABC) family, and encodes a transport protein of 1503 amino acids.…”

Frequent Mutation in the ABCC6 Gene (R1141X) Is Associated With a Strong Increase in the Prevalence of Coronary Artery Disease

“…[1][2][3][4] Most PXE patients seem random, but autosomal recessive and autosomal dominant inheritance also is observed. 5,6 The frequency of PXE in the general population is unknown, particularly because it is likely that individuals with a mild clinical phenotype will escape diagnosis.…”