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British Journal of Radiology (2006) 79, 221-225
© 2006 British Institute of Radiology
doi: 10.1259/bjr/20801330
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Full Paper

Visceral and testicular calcifications as part of the phenotype in pseudoxanthoma elasticum: ultrasound findings in Belgian patients and healthy carriers

O M Vanakker, MD 1 D Voet, MD, PhD 2 M Petrovic, MD, PhD 2 F van Robaeys, MD 3 B P Leroy, MD 1 P Coucke, PhD 1 and A de Paepe, MD, PhD 1

1 Center for Medical Genetics, 2 Department of Sonography, 3 Department of Radiology and Medical Imaging, Ghent University, Hospital, De Pintelaan 185, 9000 Ghent, Belgium

Correspondence: Anne De Paepe, Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Occasionally calcifications in abdominal organs, breasts and testicles have been reported in pseudoxanthoma elasticum (PXE) patients. In the present study, an ultrasound evaluation was performed of the abdomen and – in male patients – of the testicles in 17 PXE patients and 17 heterozygous carriers. Blood samples were taken to evaluate calcium load, liver and kidney function. Calcifications in liver, kidneys and spleen were detected in 59% of the patients and in 23.5% of healthy carriers. Parameters of kidney and liver function were normal in both groups, suggesting that the calcifications have no direct effect on organ function. Testicular ultrasound revealed parenchymous calcifications in all males investigated. Widespread, small hyperechogenic foci resembling testicular microlithiasis were seen. In some carriers, focal calcifications were identified. The current data suggest that visceral and testicular calcifications are part of the phenotype of PXE patients. Their presence in some of the healthy carriers are suggestive of subclinical manifestations in these relatives. The natural history and long-term effects of the parenchymal calcifications remain to be elucidated. As testicular microlithiasis may be associated with a higher risk for malignancy, regular clinical and ultrasound follow-up seems indicated in these patients.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Pseudoxanthoma elasticum (PXE – OMIM [Online Mendelian Inheritance in Man]# 264800) is an autosomal recessive connective tissue disorder with multiple systemic manifestations. The phenotype consists of a triad of papular lesions and increased skin laxity in the flexural areas of the body, angioid streaks in the ocular fundus with eventually retinal haemorrhages and loss of central vision, and accelerated atherosclerosis leading to cardiovascular complications [1–5]. The incidence of this rare disease has recently been estimated to be 1:75 000 [6], although this may be an underestimation due to the high variability of the phenotype. Clinical manifestations of the disease are attributed to alterations of elastic fibres within the extracellular matrix of the affected organs. These fibres undergo progressive fragmentation and mineralization, which is the histopathological hallmark of the disease [2]. Nevertheless, other components of the extracellular matrix, such as collagen, fibrillins and proteoglycans have either an abnormal morphology or distribution [7, 8].

The gene responsible for PXE (ABCC6 - MIM# 603234) is located on chromosome 16p13.1. It encodes an ATP-dependent transporter the substrate of which is as yet unknown. The relationship between this protein and the phenotype also remains to be elucidated [9–11].

It has been shown that healthy carriers of PXE have similar cutaneous abnormalities at the ultrastructural level, suggesting that a mild phenotype may be seen in these individuals [12]. Although a higher incidence of cardiovascular disease has been reported, carriers do not develop other manifestations of PXE such as cutaneous and/or retinal disease [12–14].

Occasionally, PXE patients have been reported in which calcifications in several organs, including kidney, pancreas, spleen and breasts have been observed [15–21]. Additionally, one case report has described the presence of multiple calcifications in the testicles of a 14-year-old PXE-patient [22]. These reports suggest a possible association of organ calcifications and PXE. To our knowledge, no systematic screening of patients nor of healthy carriers has been performed. We present a comprehensive ultrasound study of 17 PXE patients in whom the association between visceral and/or testicular calcifications and PXE was established. Furthermore, 17 heterozygous relatives were screened to detect whether similar lesions could be found.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Sixteen patients with clinical, molecular and biopsy-proven PXE were examined. Informed consent was obtained from all patients and the study was approved by the Ethical Committee of the Faculty of Medicine of the Ghent University Hospital. Our patient population consisted of 5 men and 12 women. Ages ranged from 18 years to 80 years with an average of 54 years.

The group of 17 heterozygous carriers included offspring as well as parents of patients (obligate carriers). Additionally, siblings of patients proven to be heterozygous carriers of an ABCC6 mutation were included. The carrier group consisted of 11 men and 6 women. Ages ranged from 16 years to 76 years with an average age of 39 years.

All index-patients and carriers were personally examined at the PXE clinic of the Center for Medical Genetics at the Ghent University Hospital. Thorough patient histories were recorded in all individuals with special consideration for signs and symptoms indicating hepatic, renal or splenic dysfunction.

The full clinical protocol used at the PXE clinic of the Center for Medical Genetics at the Ghent University Hospital, including careful dermatological, ophthalmological and cardiovascular examinations and ultrasound of the abdomen and testicles, was applied in both groups. Ultrasound examinations were performed at the Department of Sonography using a HDI 5000 system (Philips, Brussels, Belgium) with a C5-2 and a L12-5 scanhead for the examination of the abdomen and scrotum, respectively. To minimize interobserver variation three ultrasonographers performed the examinations were blinded to patient information. Serum analysis was performed to evaluate calcium load, liver and kidney function in order to exclude other aetiologies of parenchymal calcifications and to assess the possible functional effect of the lesions. Parameters measured in all individuals included serum concentrations of aspartate amino transferase (AST), amino alanine transferase (ALT), alkaline phosphatase (AF), gamma-glutamyl transpeptidase ({gamma}GT), creatinine, urea, calcium and phosphorus.

Skin biopsies were taken either in an affected skin area or at the back of the neck when no lesion was macroscopically apparent. Histological confirmation of PXE was obtained with haematoxylin and eosin, van Giesson and Von Kossa stains to detect the typical anomalies of the elastic fibre.

Molecular screening of the ABCC6 gene was performed using dHPLC (denaturing high performance liquid chromatography) (Transgenomics, Cheshire, UK) and subsequent sequencing of all ABCC6 exons in those that showed abnormal dHPLC-patterns.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Abdominal ultrasounds
Abdominal ultrasound revealed calcifications scattered throughout the parenchyma of the kidneys (8 patients), liver (4 patients) or spleen (3 patients) in 10/17 (59%) of PXE patients (Figure 1a–dGo). In those with visceral calcifications, kidneys were most frequently affected (80%). In 3 out of 10 (30%) patients, two or more organs were involved. The number of calcified lesions ranged from a few in the spleen to widely disseminated in the liver parenchyma. Calcifications were seen as hyperechogenic foci with acoustic shadowing, measuring 2–3 mm in diameter. Renal calcifications were localized in the corticomedullary junction, but also within the cortical tissue. Similar lesions could be observed in 4 out of 17 healthy carriers. Two of those had kidney calcifications while the others had lesions in the liver. Other ultrasound findings included hepatic haemangiomas and steatosis.


Figure 1
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  		Figure 1. Ultrasound images of calcified foci in several abdominal organs:(a) frontal cross-section through the abdomen with multiple calcifications in the liver of a pseudoxanthoma elasticum (PXE) patient; (b) subcostal transverse cross-section of the liver of a heterozygous carrier in which two calcifications with acoustic shadowing are seen; (c,d) frontal cross-section through the abdomen with view of multiple hyperechogenic foci in (c) the right kidney and (d) spleen of PXE patients.

 
Serum tests to evaluate kidney and liver function were performed in all patients and carriers examined. No abnormalities of either liver enzymes nor serum creatinine and urea were observed. Calcium levels were always within normal limits. None of the individuals in this study had signs or symptoms indicative of abnormal function of the liver, spleen or kidneys.

Testicular ultrasounds
Ultrasound of the scrotum was performed in four PXE patients. In three multiple widespread, small hyperechogenic foci resembling a "heaven full of stars" were identified throughout the parenchyma of both testicles (Figure 2Go). This appearance matches the criteria of classical testicular microlithiasis as described by Dell'Acqua et al [23]. One patient had only few of these lesions, compatible with limited testicular microlithiasis.


Figure 2
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  		Figure 2. Longitudinal cross-section of the testicle with scattered parenchymatous calcifications in the right testicle of a pseudoxanthoma elasticum(PXE) patient as a typical example of testicular microlithiasis.

 
However, no histological confirmation of this diagnosis was obtained since none of the patients had any complaint warranting a biopsy. No testicular tumours were detected during the examination.

In two out of 11 healthy carriers examined, focal calcifications of the testicular capsule or parenchyma were observed. The parenchymatous calcification was a small unilateral focus without acoustic shadowing. These individuals were asymptomatic. Two carriers were found to have a hyperechogenic mediastinum testis, which can be considered a normal variant.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
PXE is a rare autosomal recessive disease characterized by fragmentation and calcification of the elastic fibres. Clinical manifestations mainly consist of cutaneous, ophthalmological and cardiovascular lesions. Case reports have mentioned the occurrence of calcifications in the visceral organs, breasts and testicles in some individuals [15–21]. In this study, a standardized examination protocol comprising abdominal and testicular ultrasounds was used in 17 PXE patients to observe whether calcified lesions in these organs could be detected.

Due to the autosomal recessive inheritance of PXE, parents and children of probands are obligate carriers of one mutation in the ABCC6 gene. Previous ultrastructural studies in relatives of PXE patients have revealed cutaneous morphologic alterations similar to those seen in patients, although less severe in nature [12]. Trip et al described a higher risk of coronary artery disease in carriers of the frequent R1141X nonsense mutation [13]. These observations indicate that heterozygous carriers may have mild PXE manifestations, albeit without obvious cutaneous or ophthalmological symptoms. Therefore, ultrasound evidence of subclinical manifestations was sought in mutation carriers.

Abdominal ultrasound
The data presented suggest that visceral calcifications in the kidneys, liver and spleen are indeed part of the phenotype of PXE patients. Interestingly, similar lesions were found to be present in some of the healthy carriers, although less frequently and to a lesser extent.

All ages were represented in patients and carriers with visceral calcifications, making our findings unlikely to be attributed solely to the age of the individuals. Calcium and phosphorus load were normal in all individuals, excluding other aetiologies of visceral calcifications such as chronic granulomatous diseases (e.g. sarcoidosis), renal failure, hyper(para)thyroidism, pheochromocytoma, adrenal insufficiency or malignancy.

As serum tests for liver and kidney function revealed no abnormalities and none of the individuals examined suffered from any disturbances of renal, hepatic or splenic function, the calcified foci probably do not interfere with liver, kidney or splenic function. However, their natural history and long-term effects remain to be elucidated.

Therefore an abdominal ultrasound at the time of diagnosis may be indicated. Furthermore, regular re-evaluation with serum tests and ultrasound are advisable.

It has been previously reported that both abdominal plain radiographs and CT are unable to visualize these lesions [18]. In the only patient with renal foci in whom abdominal radiographs were performed in this study, no calcifications were visible. We did not perform CT imaging in our population and can therefore not rule out that, due to technical improvements and new developments, these lesions can now be visualized. However, since ultrasound proved to give sufficient data and comparing the costs and radiation load of both examinations, we feel that at present CT is not an added value in the work-up of a PXE patient in a clinical setting. In a research setting, however, it would be interesting to find out if these lesions are indeed visible with modern CT techniques and to evaluate their extent and characteristics in comparison with ultrasound findings. Thus, in view of all known aspects, ultrasound should be considered the investigation of first choice for detection of these calcifications on a routine basis.

Testicular ultrasounds
Testicular parenchymal calcifications were identified in all male patients so far examined. These lesions, described as bilateral, small, hyperechogenic foci, meet the ultrasound criteria of testicular microlithiasis (TM). The TM pattern is defined as usually bilateral hyperechogenic multiple small foci without acoustic shadow and with complete or partial extension to the parenchyma. Cases in which five or more foci can be demonstrated are defined as classical TM [24–27]. Cases that do not meet this criterion are designated as limited TM. The imaging diagnosis can be confirmed by showing intratubular microliths on biopsy [24–27]. Since none of our patients had either complaints or fertility problems testicular biopsies were considered unethical. TM is of special interest due to its reported association with testicular malignancy [29–36]. Nevertheless, it remains unclear whether primary testicular tumours actually occur more frequently in patients with pre-existing TM. Large prospective studies are needed to further clarify this issue. Until further data are available, it seems cautious to consider patients with a TM-like ultrasound image as having a potentially increased risk of developing a testicular malignancy and to offer regular ultrasound screening [28–34, 36].

The findings in healthy carriers were different from those in patients in their extent and/or location within the testicle. Multiple hyperechogenic foci confined to the capsule or the mediastinum testis were detected, the latter probably being a normal variant. Although anatomically this could also be compatible with calcifications in the rete testis [37], we cannot be sure of this without a biopsy which is unjustifiable in these patients.

In another carrier, we observed one parenchymatous calcification which could be considered as limited TM. The remaining parenchyma, however, was completely normal and we cannot exclude that these findings are fortuitous. Since they have, to our knowledge, not previously been described in PXE, further study on a larger group of carriers would be of interest.


   Acknowledgments
 
The authors are very grateful to all PXE patients and families for their kind collaboration. This work was supported by a grant from the Ghent University (GOA-12051203). O Vanakker is a research assistant supported by the Fund for Scientific Research – Flanders (Belgium).

Received for publication February 1, 2005. Revision received May 4, 2005. Accepted for publication July 15, 2005.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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This Article
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