Objectives Pseudoxanthoma elasticum (PXE) is a rare genetic disorder, characterised by elastic fibre degeneration and calcifi- cations in multiple organ systems. Computed tomography (CT) imaging is a potential method to monitor disease progression in PXE patients; however, this method has not been validated. The aim of this study was to correlate histological and computed tomographic findings in PXE patients to investigate the ability of CT scanning to detect these alterations. Methods Post mortem total body CT scans were obtained from two PXE patients (a 69-year-old male and 77-year-old female). Autopsy was performed, and 38 tissue samples of the first and 45 tissue samples of the second patient were extensively investigated histologically. The findings were compared with the CT scans. Results Degenerated and calcified elastic fibres and calcifications were histologically found in the skin, subcutaneous fat, heart, arteries and pleura and around the oesophagus. On CT imaging only the intradermal alterations of the skin and the larger vascular calcifications were detected. The smaller PXE-related abnormalities were not visible on CT. Conclusions With CT imaging vascular calcifications and skin alterations can be monitored in PXE patients. However, many of the subtle PXE-related abnormalities found in other organ systems during the autopsy were not visualised by CT scans. Furthermore, we extended the current knowledge on the disease location of PXE with subcutaneous, oesophageal and pleural lesions. Teaching Points � CT can be used to monitor gross vascular calcifications in PXE patients. � Many subtle PXE-related abnormalities are not visualised by CT scans. � PXE-related alterations can also be found in oesophagus, pleura and subcutaneous fat. . . . . Keywords Pseudoxanthoma elasticum Autopsy Histology Radiology Vascular calcification Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13244-018-0621-6) contains supplementary material, which is available to authorized users. * Wilko Spiering Department of Radiology, University Medical Center, Utrecht W.Spiering@umcutrecht.nl University, Utrecht, The Netherlands Department of Anatomy, University Medical Center, Utrecht Department of Pathology, University Medical Center, Utrecht University, Utrecht, The Netherlands University, Utrecht, The Netherlands Image Sciences Institute, University Medical Center, Utrecht Department of Vascular Medicine, University Medical Center, University, Utrecht, The Netherlands Utrecht University, PO Box 85500, 3508 GA Utrecht, The Netherlands 494 Insights Imaging (2018) 9:493–498 Introduction Histology Pseudoxanthoma elasticum (PXE) or Grönblad-Strandberg Tissue samples from the skin, heart, arteries, digestive system, syndrome is a rare autosomal recessive disorder characterised respiratory system, genitourinary system, haematopoietic sys- by ectopic calcifications of connective tissues . The disease tem, endocrine system and central nervous system (online is, in the majority of cases, caused by mutations in the ABCC6 supplemental Table 1) were obtained the during autopsy and gene [2–4]. These ABCC6 gene mutations result in lower fixedin4%formaldehyde. Themacroscopically calcified sam- levels of inorganic pyrophosphate leading to progressive cal- ples were subsequently decalcified using diaminoethylene cification throughout the body . tetraacetic acid solution (EDTA). Decalcification was necessary Previous studies have shown that alterations can be found to maintain the morphology of the tissue specimens. Since his- both histologically and radiologically in the skin, testis and tological evaluation of calcification is based on visualisation of blood vessels [6–10]. Furthermore, histological alterations the previously altered matrix by the calcification process, and have been described in the eyes and brain [9–11]. Using im- not the calcium ions themselves, decalcification does not influ- aging techniques, calcifications have been described juxta-ar- ence analysis . Four-micrometre slides were cut and stained ticular, in the soft tissues of the extremities and in the breast [6, with haematoxylin and eosin and, in anatomic locations where 8]. elastic fibres were expected, additional elastin van Gieson stain The combination of histology and radiology may provide was used. In non-decalcified tissue with altered elastic fibres, a insight into the extent to which the imaging findings may be von Kossa stain was used to detect calcifications. able to identify the PXE alterations in vivo, important knowl- edge for further diagnostics and research in living patients. Although some histological and radiological studies have Results been performed in PXE patients, a correlation study between the two is lacking. The aim of this study was to investigate to Skin what extent histologically determined alterations can be de- tected with computed tomography (CT) scan in PXE patients. Classical PXE skin alterations were found at the axillae of both patients, a localisation typically known for skin changes in PXE. Microscopically dense clumps of degenerated and calcified elastic fibres were found in the mid and lower der- Methods mis. On CT, these alterations were seen as thickened skin without obvious calcifications. Microscopy of the macroscop- Both tissue samples and CT images were obtained from two ically normal skin of the abdomen and extremities showed autopsy patients (a 69-year-old male and 77-year-old female) similar changes that were located in the connective tissue sep- diagnosed with PXE ante mortem. One of the patients donated ta between the subcutaneous fatty layer (Fig. 1). On CT, how- her body to science via the Department of Anatomy of the ever, no abnormalities were seen at these locations (Table 1). University Medical Centre Utrecht. From this patient, written informed consent regarding the use of her body for education- Cardiovascular system al and research purposes was obtained during life. For the other patient, relatives gave consent to the post mortem inves- The hearts of both patients showed localised degenerated tigations. Collection of the material was approved by the local and calcified elastic fibres in the area underneath the en- biobank review committee under protocol number 15–252. docardial layer, mainly present in both atria. Furthermore, some similar elastic fibres were present in the interstitial fibrous tissue between the cardiomyocytes (Fig. 2). On Radiology CT no calcifications were seen in the endo- or myocardial tissue. Calcification of the valves was not present in these Subjects were scanned post mortem on a Philips patients (Table 1). Brilliance 256-slice CT scanner (Philips Healthcare, The vascular system showed the presence of both athero- Best, The Netherlands). Tube voltage was 140 kV and sclerotic intimal lesions with calcifications and calcifications tube current 200 mAs. Non-contrast-enhanced CT scans in the medial layer and/or around the internal and external with 0.9-mm slice thickness were acquired. The CT elastic lamina of the arterial system. In the lower extremities, scans were evaluated by one radiologist (PdJ) with 14 large amounts of medial/elastic lamina calcification were pres- years of experience in reading CT scans. The radiologist ent, accompanied by intimal lesions of variable severity. Also was blinded to the autopsy results, but aware of the the gastroepiploic artery showed extensive calcification of the locations that were histologically examined. medial layer and around the elastic lamina. On CT, these Insights Imaging (2018) 9:493–498 495 Fig. 1 Skin alterations in the pseudoxanthoma elasticum. A–C: In the axillae typical pseudoxanthoma elasticum lesions were found, consisting of clumps of degenerated elastic fibres in the mid and lower dermis (A). Von Kossa stain showed calcifications of these elastic fibres (B). On the CT scan, thickenedskin(<) wasseen(C). D–F: Other localisations of the skin, macroscopically unremark- able, showed degenerated elastic fibres in the septa of the subcuta- neous fatty layer. The marked ar- ea in D is shown in E (H&E stain) and F (von Kossa stain) medial calcifications were detected as more or less circumfer- calcifications in the hippocampal area of one of the pa- ential and present over a longer track of the vascular wall. The tients were not seen (Table 1). other large and middle-sized arteries showed variable amounts of calcified elastic fibres in the media (in elastic arteries) and/ Other findings or the internal and external elastic lamina (Fig. 3). These small scattered calcified fibres were not detected on CT. In one of the patients, a kidney stone in the right kidney Furthermore, in some of the small arteries in the organs (heart, was found, an observation also made via CT. The same lung, kidney, stomach, pancreas, thyroid), more or less cir- patient also showed a calcified right adrenal gland, micro- cumferential calcification of the internal elastic lamina was scopically fitting with a myelolipoma with, or combined present. These very small vessels were not detected on CT. with, extreme calcifications and bony transformation. Besides medial/elastic lamina calcification, also many calcifi- Furthermore, small gallstones were present in the gallblad- cations were present in the atherosclerotic lesions found in der of this patient. These were seen on CT. In the other both patients. These calcifications were much more clumped patient, some degenerated and calcified fibres were found together and therefore, if large enough, detectable on CT histologically in the pleura and around the oesophagus. (Table 1). The CT showed a thickened pleura. However, since this patient also suffered from a malignancy in the lung, the cause of this thickening was probably localisation of the Central nervous system lung carcinoma and not alterations caused by PXE. No abnormalities were seen around the oesophagus on CT A lacunar infarction was found in both patients (one in (Table 1). the left frontal lobe and one in the area of the basal nuclei). Furthermore, in one patient the central white matter showed dispersion of the fibrillary matrix with Discussion clear demyelination. The subcortical white matter was unremarkable (Fig. 4). The cerebral microvasculature PXE is a systemic disease characterised by elastic fibre degen- showed sclerosis of the vascular wall, with vascular cal- eration and calcification in multiple organ systems. The pres- cifications in the area of the globus pallidus. In one of ent study combines radiological and histological findings in the patients, some calcifications were present in the hip- two PXE patients to investigate which alterations can and pocampal region. On the CT, there were nonspecific ab- which cannot be seen using CT. The study has two important normalities in the white matter area. The small vascular results. First, most of the abnormalities seen on histological calcifications in the area of the globus pallidus, present slides were not seen on the CT, except for the intradermal skin in both patients, were not seen on CT. Also the vascular alterations and part of the vascular calcifications. Second, this 496 Insights Imaging (2018) 9:493–498 Table 1 Alterations found histologically and radiologically in the two PXE patients Histology Radiology Macroscopically altered skin Degeneration and calcification of Thickened skin the elastic fibres in the mid and lower dermis Macroscopically normal skin Degeneration and calcification of – the elastic fibres in the septa between the subcutaneous fatty layer Heart Degeneration and calcification of – elastic fibres mainly underneath the endocardial layer and to a lesser extent in fibrous tissue between the cardiomyocytes Arteries (lower extremity, Both atherosclerotic intimal lesions More or less circumferential calcifications gastroepiploic artery) and calcifications in the medial layer in case of medial calcification, thick dots of calcification in case of intimal calcification Arteries (other) Small scattered calcified elastic fibres Thick dots of calcification in case of in the media and/or internal and intimal calcification external elastic lamina Atherosclerotic intimal lesions Central nervous system Lacunar infarction – Central nervous system White matter abnormalities Non-specific abnormalities in the white matter area Central nervous system Calcification of the small arteries in – the area of the globus pallidus and hippocampal area Kidney Kidney stone Kidney stone Adrenal gland Myelolipoma with calcifications and Calcified adrenal gland bony transformation Gallbladder Gallstones Gallstones Lung Some degenerated and calcified elastic Thickened pleura fibres in the pleura Oesophagus Some degenerated and calcified elastic – fibres around the oesophagus study adds to the existing knowledge regarding the abnormal- Cardiovascular system ities that can be seen in PXE patients. Degenerated and calci- fied elastic fibres were not only found in the skin, arteries, In the heart degenerated and calcified elastic fibres were pres- heart and pleura, where they have been described before, but ent subendocardially and in the interstitium between the also in the fibrous bands in between the subcutaneous fat cardiomyocytes. The presence of these altered elastic fibres tissue and around the oesophagus. in the cardiac tissue has been described before and has been suggested as a cause of restrictive cardiomyopathy and con- Skin gestive heart failure [9, 14]. The vascular system showed the presence of both athero- Besides the histological skin alterations typical for PXE, sclerotic intimal lesions with calcifications and calcifications we also found histological alterations in macroscopically present in the medial layer and/or around the internal and unaltered skin, most abundantly located in the subcutane- external elastic lamina of the vascular wall. In case of exten- ous fat. The presence of some abnormal elastic fibres in sive calcification of the medial layer or elastic lamina, on CT non-lesional skin has been described before . However, scans a more or less circumferential pattern over a longer the presence of subcutaneous lesions at these locations has segment of the vessel was seen. This pattern is comparable not been described before. A possible explanation could be to the pattern of medial calcification seen on X-rays described that most knowledge about histological skin alterations is in the scarce literature . Our findings of vascular calcifi- obtained by studies in skin biopsies, with only small cations and the combination of both atherosclerosis and me- amounts of subcutaneous fat. dial calcification are consistent with previous findings . Insights Imaging (2018) 9:493–498 497 Fig. 2 Elastic fibre alterations in the heart. a Degenerated and calcified fibres were mainly found below the endocardial layer (right side of the picture). Furthermore, similar fibres were seen in the interstitial fibrous tissue in the myocardium (left side of the picture). b Von Kossa stain showing the calcified elastic fibres. c Enlarged picture of the abnormal elastic fibres within the interstitial fibrotic tissue in the myocardium. d Enlarged picture of the abnormal elastic fibres in the subendocardial layer Central nervous system In both patients, a lacunar infarction was found. The combi- nation of PXE and lacunar infarctions of the brain has been Fig. 3 Vascular calcifications. A and B: Extensive calcifications, on the described before as a complication of small vessel disease CT scan seen as more or less circumferential calcifications in a longer segment of the vascular wall, were present around the internal elastic . Also the white matter lesions, as seen in one of our lamina and in the media of the vessels of the lower extremities [here the patients, have been described before in association with PXE anterior tibial artery (<)]; calcifications are marked with a black line in A. [11, 17, 18]. The combination of lacunar infarctions and white C and D. The same internal elastic lamina and medial calcifications were matter lesions have been described in association with cogni- visible in the gastroepiploic artery, located along the greater curvature of the stomach, in both the histology (calcifications are marked in C) and CT tive deterioration, although reports also mention extensive scan (<). E and F: In most of the other large- and middle-sized arteries, white matter lesions in a patient with normal baseline cogni- variable amounts of calcified elastic fibres were seen in the media (in tive status . On CT scans nonspecific abnormalities could elastic arteries) and/or around the internal and external elastic lamina (marked). These small calcifications could not be detected on CT scans, be found in the white matter area. For diagnostic purposes and on which also many atherosclerotic intimal calcifications were visible further research, MRI probably is a better imaging technique. (i = intima, m = media, a = adventitia; dotted lines indicate internal and external elastic lamina) Other findings A kidney stone was found in one of the patients. A possible knowledge, degenerated and calcified elastic fibres have not relation between PXE and nephrolithiasis has been suggested been described in these locations before. before . However, in most of the patients described An important limitation of this study is the limited num- phosphocalcic abnormalities were present, which was not ber of bodies studied, which can be explained by the low the case in our patient. Since nephrolithiasis is not a rare con- incidence of the disease and low autopsy rate in dition, it is not unlikely that this is a coincidental finding. In The Netherlands. Due to this small number of patients, it the same patient, also gallstones and a calcified adrenal gland is possible that by chance we selected two patients in were found. It is unknown to which extent this can be related which many abnormalities were not seen on CT scans, to PXE. Furthermore, in the other patient some calcified fibres while in larger series of patients this would not have been were found in the pleura and around the oesophagus. To our the case. Therefore, our findings need confirmation in a 498 Insights Imaging (2018) 9:493–498 summary of the 2010 PXE international research meeting. Am J Med Genet A 155A:1317–1526 2. Bergen AA, Plomp AS, Schuurman EJ et al (2000) Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet 25:228–231 3. Le Saux O, Urban Z, Tschuch C et al (2000) Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet 25:223–227 4. Ringpfeil F, Lebwohl MG, Christiano AM, Uitto J (2000) Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) reporter. Proc Natl Acad Sci U S A 97:6001–6006 5. Jansen RS, Duijst S, Mahakena S et al (2014) ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol 34:1985–1989 Fig. 4 Cerebral white matter lesions. a Histological slides (Luxol fast 6. Bercovitch L, Schepps B, Koelliker S, Magro C, Terry S, Lebwohl blue-Pas stain) showed dispersion of the matrix with extensive demyelin- M (2003) Mammographic findings in pseudoxanthoma elasticum. J ation in the central white matter. Normal myelination is seen subcortically Am Acad Dermatol 48:359–366 and in the area around the basal nuclei (*). c = cortex, v = ventricle. b The 7. Bercovitch RS, Januario JA, Terry SF et al (2005) Testicular CT scan of the patient showed nonspecific white matter abnormalities (<) microlithiasis in association with pseudoxanthoma elasticum. Radiology 237:550–554 8. James AE Jr, Eaton SB, Blazek JV, Donner MW, Reeves RJ (1969) Roentgen findings in pseudoxanthoma elasticum (PXE). Am J larger series of patients. Nevertheless, the findings in our Roentgenol Radium Ther Nucl Med 106:642–647 patients during autopsy are comparable to those described 9. Miki K, Yuri T, Takeda N, Takehana K, Iwasaka T, Tsubura A in the literature. Furthermore, we did not study the eyes of (2007) An autopsy case of pseudoxanthoma elasticum: histochem- the patients. However, most of the ocular findings in PXE ical characteristics. Med Mol Morphol 40:172–177 (peau d’orange, angioid streaks, chorioretinal atrophies) 10. Nolte K (2000) Sudden cardiac death owing to pseudoxanthoma elasticum: a case report. Hum Pathol 31:1002–1004 can already be diagnosed in living patients using a variety 11. Fasshauer K, Reimers CD, Gnau HJ, Strempel I, Rossberg C (1984) of diagnostic techniques . It is doubtful whether CT, Neurological complications of Grönblad-Strandberg syndrome. J with a relatively low resolution for a small organ such as Neurol 231:250–252 the eye, can contribute to these diagnoses. 12. Burke AP, Taylor A, Farb A, Malcom GT, Virmani R (2000) Coronary calcification: insights from sudden coronary death vic- In conclusion, autopsy of two PXE patients revealed tims. Z Kardiol 89(suppl 2):49–53 degenerated and calcified elastic fibres and calcifications in 13. Lebwohl M, Schwartz E, Lemlich G, Lovelace O, Shaikh-Bahai F, skin, heart and arteries, but also in between the subcutaneous Fleischmajer R (1993) Abnormalities of connective tissue compo- fat tissue, in the pleura and around the oesophagus, locations nents in lesional and non-lesional tissue of patients with pseudoxanthoma elasticum. Arch Dermatol Res 285:121–126 where they have not been described before. Only the intrader- 14. Navarro-Lopez F, Llorian A, Ferrer-Roca O, Betriu A, Sanz G mal and vascular calcifications were seen on CT. Our results (1980) Restrictive cardiomyopathy in pseudoxanthoma elasticum. indicate that CT can be used to study vascular calcifications in Chest 78:113–115 this patient population. However, while doing so, one should 15. Orr D (1978) Correlation of radiographic and histologic findings in keep in mind that small calcifications are not visible using this arterial calcification. Invest Radiol 13:110–114 16. Mendelsohn G, Bulkley BH, Hutchins GM (1978) Cardiovascular technique. manifestations of pseudoxanthoma elasticum. Arch Pathol Lab Med 102:298–302 Compliance with ethical standards 17. Pavlovic AM, Zidverc-Trajkovic J, Milovic MM et al (2005) Cerebral small vessel disease in pseudoxanthoma elasticum: three cases. Can J Neurol Sci 32:115–118 Conflict of interest None to declare. 18. Messis CP, Budzilovich GN (1970) Pseudoxanthoma elasticum report of an autopsied case with cerebral involvement. Neurology 20:703–709 Open Access This article is distributed under the terms of the Creative 19. Fabre B, Bayle P, Bazex J, Durand D, Lamant L, Chassaing N Commons Attribution 4.0 International License (http:// (2005) Pseudoxanthoma elasticum and nephrolithiasis. J Eur creativecommons.org/licenses/by/4.0/), which permits unrestricted use, Acad Dematol Venereol 19:212–215 distribution, and reproduction in any medium, provided you give 20. Georgalas I, Tservakis I, Papaconstaninou D, Kadara M, Koutsandrea appropriate credit to the original author(s) and the source, provide a link C, Ladas I (2011) Pseudoxanthoma elasticum, ocular manifestations, to the Creative Commons license, and indicate if changes were made. complications and treatment. Clin Exp Optom 94:169–180 References Publisher’sNote 1. Uitto J, Bercovitch L, Terry SF, Terry PF (2011) Pseudoxanthoma Springer Nature remains neutral with regard to jurisdictional claims in elasticum: progress in diagnostics and research towards treatment: published maps and institutional affiliations.
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Published: Jun 1, 2018
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