Pseudoxanthoma Elasticum

A number sign (#) is used with this entry because in the overwhelming majority of cases of pseudoxanthoma elasticum (PXE), homozygous or compound heterozygous mutations are found in the ABCC6 gene (603234), i.e., PXE is an autosomal recessive disorder. However, carriers of heterozygous mutation in ABCC6 manifest partial manifestations of the disorder (177850). It is thought that instances in which the disease occurs in 2 generations can be attributed to pseudodominance (Bergen, 2006; Ringpfeil et al., 2006; Chassaing et al., 2005; Miksch et al., 2005).

Polymorphisms in the genes encoding xylosyltransferase, XYLT1 (608124) and XYLT2 (608125), have been reported to modify the severity of PXE.

Description

Pseudoxanthoma elasticum is an inherited multisystem disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Bruch membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye, including peau d'orange, angioid streaks, and choroidal neovascularizations (CNVs); of the skin, including soft, ivory colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces; and of the cardiovascular system, with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings (summary by Finger et al., 2009).

Generalized arterial calcification of infancy-2 (GACI2; 614473) is an allelic disorder, also caused by homozygous or compound heterozygous mutation in the ABCC6 gene; it has been suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders (Nitschke et al., 2012).

Clinical Features

Rigal (1881) is credited with the first description of the skin changes in PXE, and Balzer (1884) provided the first autopsy report. The term 'pseudoxanthoma elasticum' was established by Darier (1896), who histologically demonstrated an abnormality in elastin. Gronblad (1929), a Swedish ophthalmologist, and Strandberg (1929), a Swedish dermatologist, established the relationship of PXE and angioid streaks in the retina (McKusick, 1972).

Goodman et al. (1963) provided a detailed clinical and histopathologic study of 12 patients with PXE. They noted that the condition had been referred to by several different names since it was first described in 1881. Eight of 12 patients noted skin changes since early childhood, usually on the neck and in the axilla. Changes included accentuated fine lines, redundant skin folds, and lesions consisting of yellowish papules or plaques. Skin changes were also present in the inguinal folds, antecubital and popliteal spaces, and oral, rectal, and vaginal mucosa. Ocular involvement included pigmentary changes, angioid streaks, chorioretinal scarring, and some loss of vision. Five of the 12 patients had gastrointestinal bleeding. Arteriography demonstrated narrowing or occlusion of peripheral arteries with marked collateral circulation, particularly in the upper extremities. Histopathologic studies of skin, heart, and vessels showed calcium deposition in elastic fibers.

Cartwright et al. (1969) described metachromatic fibroblasts in PXE. By electron microscopy, Ross et al. (1978) demonstrated that the changes in elastic fibers in individuals with PXE involve elastin whereas the microfibrillar component is unchanged. The elastin had a granular appearance, an increased affinity for cations, and often demonstrated increased density presumed to represent foci of calcification. Similar changes were found in clinically unaffected relatives. In 3 families the inheritance was consistent with the autosomal recessive mode and 1 of the presumed heterozygotes showed electron microscopic changes. In 1 kindred (reported also by Altman et al., 1974), the inheritance was apparently more complex than either autosomal dominant or recessive.

McKusick (1972) presented autopsy findings of endocardial thickening in PXE with degeneration and calcification of elastic fibers and with collagenosis similar to that seen in the skin. Reviewing some of the same autopsy cases, Mendelsohn et al. (1978) emphasized the severe atherosclerosis present in all, resembling that encountered routinely. Fragmentation and degeneration of the elastic laminae of muscular arteries was followed by vascular calcification which could not be distinguished morphologically from Monckeberg arteriosclerosis. There was striking intimal fibroelastotic thickening, particularly in intrarenal arteries. Like McKusick (1972), Mendelsohn et al. (1978) emphasized the striking endocardial changes, e.g., in the right atrium.

Elejalde et al. (1984) described a 30-year-old woman with PXE who was followed during pregnancy with several fetal ultrasonographic examinations; these showed normal development up to week 26, followed by a marked deceleration of fetal growth. The ultrasonographic appearance of the placenta was abnormal at all times. The baby, born after 36 weeks, was small for gestational age due probably to placental abnormality: the cotyledons were small and more numerous than normal; one-third of the placenta was hypoplastic or atrophic with focal calcification; and striking abnormalities of the elastic lamellae were found in the maternal vessels. Fournier (1984) reported a well-studied patient with PXE from an isolate in the Swiss Valais canton and by genealogic research demonstrated relatedness of several affected families in the region. Livedo reticularis and microaneurysms of intrarenal arteries were observed.

Challenor et al. (1988) described a 27-year-old man with PXE who presented with pulmonary edema resulting from restrictive left ventricular cardiomyopathy caused by calcified endocardial bands. The bands were resected as far as possible and the involved mitral valve was replaced by a heterograft. A year later calcification of the heterograft forced its replacement by a St. Jude prosthesis. Relief of symptoms was satisfactory.

Fukuda et al. (1992) described a 54-year-old woman with PXE who over a year of observation developed tight mitral stenosis without regurgitation after having moderate mitral regurgitation due to mitral valve prolapse. Endocardial changes of characteristic type were demonstrated by myocardial biopsy of the right ventricle. It was thought that the echocardiographic findings differed from those in classic rheumatic mitral stenosis. Lebwohl et al. (1993) described 4 patients who presented with premature cardiovascular disease and had angioid streaks but no clinically discernible skin changes of PXE. Characteristic fragmentation and clumping of elastic fibers in the middle and deep dermis with calcification of elastic tissue was demonstrated in all 4 patients. Two of the patients were sisters, aged 27 and 39 years. The younger sister had 4-vessel coronary artery bypass surgery. Multiple arterial biopsies showed calcification of the internal elastic laminae. A 41-year-old brother was subsequently found to have angioid streaks. The father, who died at the age of 69, had a history of retinal hemorrhage.

In a nationwide study in South Africa and Zimbabwe, Viljoen et al. (1987) identified 64 patients with PXE. In the opinion of these workers, 39 of the patients comprised a distinct clinical subgroup of PXE characterized by autosomal recessive inheritance and severe visual impairment out of proportion to the degree of involvement of the skin. In 40% of individuals, severe hypertension and occasionally angina or claudication were also present. The 39 affected individuals were found exclusively among persons of Afrikaner descent. Viljoen et al. (1987) noted that the 'Afrikaner' form and other forms of PXE are indistinguishable on histology, electron microscopy, or biochemistry, and that clinical differences may not be significant. For example, McKusick (1960) had pointed out the occurrence of inconspicuous skin changes despite severe ocular changes. De Paepe et al. (1991) reported on the clinical and genetic characteristics of 26 Belgian and 32 Afrikaner families with PXE. The phenotype in both groups was characterized by severe ophthalmologic manifestations with milder, variable cutaneous and vascular symptoms. The authors reiterated the suggestion that the PXE phenotype in these Belgian and Afrikaner families is distinct from previously described PXE phenotypes.

There have been isolated case reports of arterial and skin calcification in mammograms of patients with pseudoxanthoma elasticum, and unpublished anecdotes of many women with PXE undergoing breast biopsy for evaluation of microcalcifications. Bercovitch et al. (2003) systematically evaluated mammography and breast pathology in 51 women with confirmed PXE and compared them with those of a control sample of 109 women without PXE. Breast density, skin thickening, skin microcalcifications, vascular calcification, breast microcalcifications and macrocalcifications, and masses were evaluated specifically. The PXE and control groups were similar in age and indications for mammography. Bercovitch et al. (2003) found a statistically significant increase in skin thickening, vascular calcification, and breast microcalcifications in the PXE group (P less than 0.001 each). Breast density, masses, macrocalcifications, and skin calcification did not differ statistically in the 2 groups, but no control patient had axillary calcification, or both vascular calcification and microcalcifications (p less than 0.001). About 1 in 7 of the patients with PXE demonstrated at least 3 of the following: microcalcifications, skin calcifications, vascular calcification, and skin thickening; however, none of the control group did. Histopathologic findings of breast tissue showed calcification of dermal elastic fibers, subcutaneous arteries, and elastic fibers of the deep fascia and interlobular septae of the fat adjacent to breast parenchyma. Bercovitch et al. (2003) concluded that breast microcalcification and arterial calcification are not rare in the normal population and are not of diagnostic value. However, the presence of both of these findings, especially with skin thickening or axillary skin calcification, should suggest a diagnosis of PXE. The majority of breast calcifications in PXE are benign.

Orssaud et al. (2015) reviewed the nature and age of onset of ophthalmologic manifestations in 40 consecutive patients with PXE. The mean age of patients was 53.32 years. Best corrected visual acuity (BCVA) was equal to or less than 20/50 in at least 1 eye in 73.3% of patients over the age of 52 and in 20% of patients younger than age 52. Angioid streaks were observed in 38 patients (93.75%). Macular involvement was observed for the first time at a mean age of 44.28 years. Neovascularization was observed in 17 patients (mean age, 51.70 years), all with poor BCVA. The authors noted that in addition to the well-known findings of peau d'orange and comet lesions, other PXE features include chorioretinal atrophy, subretinal fluid independent of CNV, pattern dystrophy-like changes, debris accumulation under the RPE, reticular drusen, and a decreased fluorescence on late-phase indocyanine green angiography.

Legrand et al. (2017) performed a molecular analysis on 458 French PXE probands who were clinically evaluated using the Phenodex score (PS). Among the 220 cases with a complete PS score, there was a higher prevalence of eye features in Caucasian patients (p = 0.03) and more severe eye and vascular phenotype in patients with loss-of-function variants (p = 0.02 and 0.05, respectively). Nephrolithiases and strokes, absent from the PS, were prevalent features of the disorder (11% and 10%, respectively).

Intrafamilial Phenotypic Variability

Le Boulanger et al. (2010) studied a nonconsanguineous French family in which an older brother developed uncomplicated PXE in adolescence, whereas a younger brother died of a condition 'strikingly reminiscent' of generalized arterial calcification of infancy (GACI2; 614473) at 15 months of age. The younger brother had a myocardial infarction complicated by heart failure at 6 months of age, and skin biopsy at 1 year of age for evaluation of a possible connective tissue disorder showed elastic fiber dystrophy, with clumped and fragmented fibers in the mid dermis, as well as calcifications on the elastic fibers and sporadically in vessel walls of the subcutis. At 15 months of age, he had a second, fatal MI, and autopsy showed fibrosis of the coronary arteries with calcifications involving the intima, internal elastic lamina, and media. At 28 years of age, the older brother presented for evaluation of yellowish papules on his neck; he had no cardiovascular symptoms and cardiac examination and echocardiography were normal. Skin samples from the brother with PXE showed heavy staining of mineralized mid-dermal elastic fibers, with active MGP (154870) and fetuin-A (138680) antibodies, and fetuin-A also showed striking staining of the subepidermal area. All arteries in autopsy samples from the brother with GACI showed the same immunohistochemical profile, as well as calcifications.

Diagnosis

Lebwohl et al. (1987) biopsied scars as well as flexural skin from 10 patients with angioid streaks but without cutaneous findings indicative of PXE. In 6 of the 10 patients, scar biopsies showed fragmentation and clumping of elastic tissue in the deep dermis. Three patients also had histologic changes of PXE in biopsy specimens of flexural skin that appeared normal. The authors concluded that scar biopsies may be useful in diagnosis when PXE is suspected despite the absence of typical skin lesions.

In a report of a consensus conference on PXE, Lebwohl et al. (1994) stated that histologic evidence of calcified elastic fibers is essential for diagnosis. The group proposed a provisional classification system of PXE patients who may lack one or more of the 3 major criteria: skin, eye, or cardiovascular involvement. However, the group also noted that in time, all patients with PXE tend to merge into a single classic phenotype with all 3 features, and that separation into subtypes based on phenotype is difficult.

Struk et al. (1997) noted that the 'gold standard' for diagnosis of PXE is positive von Kossa staining showing calcification and fracture of elastic fibers in biopsy material from affected skin.

Plomp et al. (2010) reviewed the major clinical signs of PXE and proposed an updated classification system for the disorder, including revised diagnostic criteria. Diagnostic criteria included skin findings confirmed by skin biopsy, ocular findings corroborated by funduscopy, and mutation analysis of the ABCC6 gene. Additional minor criteria included the findings of 'comets' in the retina or 'pigmented wing' signs in the retina. Patients can be classified as having a definite, probable, or possible diagnosis based on the number of signs present.

Differential Diagnosis

The occurrence of angioid streaks in homozygous thalassemia and in sickle cell anemia has been attributed to the deposition of iron in Bruch membrane behind the retina. Severe ophthalmologic complications like those of PXE may occur in some cases (Aessopos et al., 1989). Angioid streaks in hemochromatosis are presumably also a reflection of iron deposits. The occurrence of angioid streaks with Paget disease of bone (167250) and with tumoral calcinosis with hyperphosphatemia (211900) may be related to the deposition of calcium in a relatively normal Bruch membrane. Angioid streaks are said to occur with lead poisoning (Clarkson and Altman, 1982). Aessopos et al. (1992) suggested that beta-thalassemia must be considered in the differential diagnosis of PXE because of the occurrence of PXE-like skin lesions as well as angioid streaks. In 62 patients with homozygous beta-thalassemia major and 38 with beta-thalassemia intermedia, they found diagnostic skin lesions in 16 patients. Angioid streaks were found in 20 of the 100 patients, and both PXE skin lesions and angioid streaks were found in 10 of the patients; in all, 26 had either one or both of these manifestations. A positive correlation was found between the presence of one or both types of lesion and age of the patients; there were no differences in regard to ferritin and hematocrit levels, number of transfused units, chelation therapy, and splenic status between patients with or without the findings of PXE. One might wonder about iron loading as the mechanism of the PXE-like changes. Angioid streaks were described in homozygous sickle cell disease by Nagpal et al. (1976), Hamilton et al. (1981), and others. Aessopos et al. (2002) reviewed elastic tissue abnormalities resembling PXE in beta-thalassemia and sickling syndromes.

Hamlin et al. (2003) reported the clinical and histopathologic manifestations of 10 beta-thalassemia patients with PXE-like skin lesions in combination with ocular and/or vascular symptoms and calcified elastic fibers. No disease-causing variant was found in the ABCC6 (603234) gene, indicating that this was a phenocopy of PXE. Hamlin et al. (2003) discussed the hypothesis that as iron loading progresses in beta-thalassemic patients, the capacity for the transport and storage of iron may be exceeded, and a fraction of iron that is not bound to transferrin or ferritin may promote the generation of free radicals, which are in turn propagators of oxidation-related damage to various organs and tissues, including elastin-rich tissues.

Inheritance

The assessment of inheritance in PXE has been complicated by clinical heterogeneity and variable age of onset (Neldner, 1988).

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%. Their mutation analysis confirmed an earlier haplotype-based analysis and conclusions regarding a recessive-only mode of inheritance in PXE (Cai et al., 2000) through the identification of 2 mutated alleles in all individuals with PXE who appear in either consecutive or alternating generations of the same family. Their study demonstrated that the full phenotypic expression of the disorder requires 2 defective allelic copies of ABCC6 and that pseudodominance is the mode of transmission in presumed autosomal dominant families (i.e., the second parental disease allele 'marries into' the family). The apparent frequency of this mechanism was approximately 7.5% in their family cohort. Miksch et al. (2005) stated that in their families no heterozygote for a large deletion showed any apparent clinical sign of PXE according to category I diagnostic criteria.

To determine the exact mode of inheritance of PXE, Ringpfeil et al. (2006) identified 7 pedigrees with affected individuals in 2 different generations and sequenced the entire coding region of ABCC6 in affected persons and in presumed carriers with a limited phenotype, as well as unaffected family members. Two allelic mutations were identified in each individual with unambiguous diagnosis of PXE, as well as in those with only minimal clinical signs suggestive of PXE but with positive skin biopsy. Missense mutations were frequently detected in the latter cases. Ringpfeil et al. (2006) concluded that PXE is inherited as an autosomal recessive trait and that those instances in which the disease occurs in 2 generations can be attributed to pseudodominance. Bergen (2006) maintained that this and other work such as that of Chassaing et al. (2005) and Miksch et al. (2005) puts an end to the 'autosomal dominant segregation myth' (see HISTORY).

Pathogenesis

Since the ABCC6 gene (603234) is expressed primarily, if not exclusively, in the liver and kidneys, Ringpfeil et al. (2001) suggested that PXE is a primary metabolic disorder with secondary involvement of elastic fibers, a situation comparable to the secondary involvement of connective tissue elements in homocystinuria (236200) and alkaptonuria (203500).

ABCC6 is a member of the large ATP-dependent transmembrane transporter family. Chassaing et al. (2005) commented that the association of PXE to ABCC6 efflux transport alterations raised a number of pathophysiology hypotheses, among them the idea that PXE is a systemic metabolic disease resulting from lack or accumulation over time in the bloodstream of molecules interacting with the synthesis, turnover, and/or maintenance of extracellular matrix (ECM).

Findings in mouse models (see ANIMAL MODEL) have also indicated that PXE is a systemic metabolic disease (Jiang et al., 2009).

Mapping

In an abstract presented at the Fifth International Workshop on Human Chromosome 16, on 3-4 March 1997 in Toronto, and in a subsequent full publication, Struk et al. (1997) reported a genomewide screen on a collection of 38 families with 2 or more sibs with PXE. They used allele-sharing algorithms, followed by high-resolution mapping and analysis by conventional linkage algorithms in recessive and dominant families. Excess allele-sharing was found on the short arm of chromosome 16 and confirmed by maximum-likelihood linkage analysis, localizing the disease gene in recessive families to a 3.0-cM region on 16p13.1 with a maximum 2-point lod score of 19.0. In dominant families, linkage to the same region with a maximum 2-point lod score of 3.6 was observed. Struk et al. (1997) predicted that allelic heterogeneity with different variants of a single disease gene residing on 16p13.1 accounts for both recessive and dominant forms of PXE.

In a family from a genetically isolated population in the Netherlands suffering from autosomal recessive PXE, van Soest et al. (1997) combined homozygosity mapping and genome scanning to map the PXE1 locus to 16p13.1. Initially, homozygosity was found in 2 or 3 patients with up to 20 markers, among which was D16S292 located in 16p13.1. Refined and more extensive family screening of the latter region showed close linkage without recombination with the marker D16S764 (maximum lod = 6.27). Despite clear autosomal recessive inheritance of the ocular symptoms in this disorder, vascular symptoms appeared in 40 to 50% of the heterozygotes.

Le Saux et al. (1999) performed linkage analysis on 21 families with PXE using 10 polymorphic markers located on 16p13.1. They localized the gene to an 8-cM region of 16p13.1 between markers D16S500 and D16S3041 with a maximum lod score of 8.1 at a recombination fraction of 0.04 for marker D16S3017. They found no evidence of locus heterogeneity. Haplotype studies of 36 PXE families identified several recombinations that further confined the PXE gene to a region of less than 1 cM between markers D16S3060 and D16S79. The PXE locus was identified within a single YAC clone and several overlapping BAC recombinants.

Molecular Genetics

In several families with PXE, Ringpfeil et al. (2000), Bergen et al. (2000), and Le Saux et al. (2000) identified mutations in the ABCC6 gene. Of 4 families with autosomal recessive inheritance of PXE reported by Ringpfeil et al. (2000), 1 was compound heterozygous for mutations in the ABCC6 gene (see, e.g., R1141X, 603234.0001), 1 family was hemizygous for the R1141X mutation, and 2 families were homozygous for mutations. Of 4 so-called sporadic cases, 1 was compound heterozygous and 3 appeared heterozygous for mutations in the ABCC6 gene. Bergen et al. (2000) identified mutations in the ABCC6 gene in 2 sporadic patients with PXE (see, e.g., 603234.0009), 4 families with PXE that appeared to be autosomal dominant (see, e.g., 603234.0008), and 1 family with autosomal recessive PXE (603234.0007). Le Saux et al. (2000) identified mutations in the ABCC6 gene in 5 families with autosomal recessive PXE and in 1 sporadic case (see, e.g., 603234.0001 and 603234.0002). The R1141X mutation (603234.0001) was found in families segregating autosomal recessive PXE and in families with expressing heterozygotes.

Using multiplex ligation-dependent probe amplification (MLPA) to analyze 35 PXE patients with incomplete ABCC6 genotypes after exonic sequencing, Costrop et al. (2010) identified 6 multiexon deletions and 4 single-exon deletions and were thus able to characterized 25% of the unidentified disease alleles. The findings illustrated the instability of the ABCC6 genomic region and stressed the importance of screening for deletions in the molecular diagnosis of PXE.

In a 28-year-old French man with pseudoxanthoma elasticum who had a younger brother who died of generalized arterial calcification of infancy (GACI2; 614473) at age 15 months, Le Boulanger et al. (2010) identified compound heterozygosity for missense mutations in the ABCC6 gene (603234.0025 and 603234.0026), which were also found in heterozygosity in each of his unaffected parents, respectively. No disease-causing mutations were found in the ENPP1 gene (173335), which is known to cause GACI1 (208000). Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. Le Boulanger et al. (2010) concluded that GACI may represent an atypical and severe end of the vascular phenotypic spectrum of PXE.

PXE-Associated Retinopathy

Choroidal neovascularization (CNV) in PXE-associated retinopathy is believed to be mediated by the action of VEGF (192240). Zarbock et al. (2009) evaluated the distribution of 10 SNPs in the promoter and coding region of the VEGFA gene in DNA samples from 163 German patients affected by PXE and in 163 healthy control subjects. Haplotype analysis identified an 8-SNP haplotype CTGGCCCC that was associated with PXE. Furthermore, 5 SNPs showed significant association with severe retinopathy. The most significant single SNP association was -460C-T (rs833061, OR = 3.83, 95% CI 2.01-7.31, corrected p = 0.0003). Logistic regression analysis identified the rs833061 and 674C-T variant (rs1413711; OR = 3.21, 95% CI 1.70-6.02, corrected p = 0.004) as independent risk factors for development of severe retinopathy. Zarbock et al. (2009) suggested an involvement of VEGF in the pathogenesis of ocular PXE manifestations.

Modifier Genes

Schon et al. (2006) reported that polymorphisms in the XYLT1 and XYLT2 genes (608124.0001 and 608125.0001, respectively) modify the severity of PXE.

Population Genetics

Struk et al. (1997) estimated that the prevalence of PXE, both the recessive and dominant forms, is 1 in 70,000 to 100,000.

In a cohort of 122 unrelated PXE patients from various countries, Le Saux et al. (2001) identified a G1321S missense mutation in the ABCC6 gene (603234.0021). The G1321S mutation was detected in heterozygosity in 1 of 74 United States alleles, for an allele frequency of 1.4%, but was not found in the European population.

Hu et al. (2003) demonstrated a founder effect for the R1141X mutation (603234.0001) in the Netherlands. They identified the mutation in 19 alleles in 16 Dutch patients with PXE, in heterozygous, homozygous, or compound heterozygous form. Expression of the normal allele in heterozygotes was predominant; no or very low expression was found in homozygotes. The mutation induced instability of the aberrant mRNA. Hu et al. (2003) suggested that the PXE phenotype of the R1141X mutation most likely results from complete loss of function or functional haploinsufficiency of ABCC6.

Animal Model

Gorgels et al. (2005) generated Abcc6 -/- mice and showed by light and electron microscopy that Abcc6 -/- mice spontaneously developed calcification of elastic fibers in blood vessel walls and in Bruch membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6 -/- mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. Gorgels et al. (2005) concluded that the phenotype of the Abcc6 -/- mouse shares calcification of elastic fibers with human PXE pathology, and supports the hypothesis that PXE is a systemic disease.

Jiang et al. (2009) found that grafting of wildtype mouse muzzle skin onto the back of Abcc6-knockout mice resulted in abnormal mineralization of vibrissae consistent with PXE, whereas grafting of Abcc6-knockout mouse muzzle skin onto wildtype mice did not. The data implied that PXE does not result from localized defect based on resident cellular abnormalities but from a change of metabolite(s) in serum. These findings implicate circulatory factors as a critical component of the mineralization process and supported the notion that PXE is a secondary mineralization of connective tissues. In addition, the findings suggested that the abnormal mineralization process could possibly be countered or even reversed by changes in the homeostatic milieu.

History

Autosomal Dominant Inheritance

Pope (1974) suggested that there are 2 dominant and 2 recessive forms of PXE (see below).

Neldner (1988) concluded that 97% of his patients had autosomal recessive inheritance. His conclusion did not allow for new mutation dominant cases.

In a report of a consensus conference, Lebwohl et al. (1994) stated that both autosomal dominant and autosomal recessive forms of PXE exist, and that no clinical features can distinguish between the 2 disorders.

Struk et al. (1997) stated that an autosomal dominant pattern of transmission of PXE occurs in approximately 10% of affected families.

Plomp et al. (2004) reviewed the literature on autosomal dominant PXE. They studied in detail, both clinically and by DNA studies, a selection of potentially autosomal dominant pedigrees from a patient population comprising 59 probands and their relatives. Individuals were considered to have definite PXE if they had 2 of the following 3 criteria: characteristic ophthalmologic signs, characteristic dermatologic signs, and positive skin biopsy. In the literature, Plomp et al. (2004) found only 3 families with definite PXE in 2 successive generations and no families with definite PXE in 3 or more generations. Their own data set included 3 putative autosomal dominant families. Extensive DNA studies revealed a mutation in only 1 ABCC6 allele in the patients of these 3 families. Only 1 of the families showed definite PXE in 2 generations. Linkage studies revealed that pseudodominance was unlikely in this family. In the other 2 families, autosomal dominant PXE could not be confirmed after extensive clinical examinations and application of the criteria, since definite PXE was not present in 2 or more generations. Plomp et al. (2004) concluded that the inheritance pattern in PXE is autosomal recessive in the overwhelming majority of families.

Hu et al. (2004) cited the investigation of Plomp et al. (2004) as indicating that autosomal dominant inheritance of PXE can be expected in approximately 2% of cases.

Classification

Pope (1974) suggested that there are 2 dominant and 2 recessive forms of PXE. The type I recessive form was characterized by moderate vascular and retinal degeneration accompanied by cutaneous lesions. The type II recessive form was characterized by generalized skin changes with no blood vessel or ocular manifestations, and was considered rare, being present in 3 of 121 probands. Individuals with the type I dominant form had severe retinal and cardiovascular degeneration, accompanied by the cutaneous features. Those with the type II dominant form had mild cardiovascular and retinal changes together with hyperextensible joints, blue sclerae, and a high arched palate.

On the basis of his own extensive experience and that reported in the literature, Neldner (1988) provided a critique of the Pope 4-subtype classification. Whereas only 47% of 121 patients studied by Pope in the U.K. were thought to have the recessive form, the more general experience is that the recessive form of PXE is by far the more frequent.

Other Inheritance

Berlyne et al. (1961) suggested that PXE may be inherited as a partial X-linked recessive (i.e., that the gene may be on a part of the X chromosome homologous with part of the Y chromosome). If such were the case, patients in any one sibship would tend always to be of the same sex. This mode of inheritance was not supported by later work.