Dystrophic calcinosis cutis in pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a genetic disorder in which elastic fibers become calcified with prominent cutaneous, ocular, and cardiovascular features. Calcinosis cutis is an acquired disorder of calcium deposition in cutaneous tissues that occurs as one of the following forms: dystrophic, metastatic, idiopathic, and iatrogenic. We report a case of a woman with PXE who developed widespread dystrophic calcinosis cutis in areas affected by PXE. Although tumoral calcification and nephrolithiasis have been reported in patients with PXE, only one other case in the English-language literature of PXE and calcinosis cutis has been reported and this case was characterized by small, milia-like papules on the front of the neck, without significant discomfort, whereas our patient had widespread involvement that was very painful and pruritic. On 6-month follow-up, this patient had only mild improvement after treatment with an anti-itch lotion and aluminum hydroxide, with which she was noncompliant.     

Pseudoxanthoma elasticum: biopsy of clinically normal skin in the investigation of patients with angioid streaks

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by fragmentation and calcification of elastic fibres with resultant pathological changes in the dermis, Bruch's membrane and blood vessels. Defects in Bruch's membrane produce angioid streaks on the retina but this appearance is not pathognomonic of PXE. Biopsy of clinically normal skin or scar tissue in patients with angioid streaks may show the histological features of PXE. OBJECTIVES: To test the hypothesis that biopsy of clinically normal skin is a useful investigation in patients with angioid streaks. METHODS: This prospective study investigated 18 consecutive patients with angioid streaks. Each patient underwent a full dermatological examination and was investigated for diseases known to be associated with angioid streaks. Axillary skin biopsies were taken from 14 consenting patients. RESULTS: Typical PXE was found in 11 patients. No other diseases associated with angioid streaks were identified. Five patients had angioid streaks in the absence of systemic disease. Two patients had nondiagnostic dermatological features which were not clarified by histology. Two of the 11 patients with PXE showed histological evidence of PXE from clinically normal axillary skin. However, in both cases flexural skin elsewhere showed the typical clinical and histological features of PXE. CONCLUSIONS: This study demonstrates the association between angioid streaks and PXE. However, it does not support the hypothesis that biopsy of normal-looking skin is helpful in the investigation of adult patients with angioid streaks.     

Pseudoxanthoma elasticum: case report with arterial stiffness evaluated by a research cardiovascular profiling system

Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder characterized by calcification of elastic tissue, affecting the skin, the eyes and vascular system. The aim of our study was to specify the cardiovascular changes in a case of pseudoxanthoma elasticum by a non-invasive haemodynamic evaluation. We present a 50-year-old woman with a clinical diagnosis of pseudoxanthoma elasticum. Except for hypertension, treated over the past four years, there was no other modifiable cardiovascular risk factor. The patient had a familiar history of early cardiovascular death. In the physical examination, typical skin lesions were present and also an angioid streak of the retina. The patient and a control group were evaluated by the CR-2000 Research Cardiovascular Profiling System. A?lower elasticity in large arteries (p = 0.006), a higher cardiac output (p = 0.006) and a higher total vascular impedance (p = 0.006) were observed with respect to the control group. There was no difference comparing this value with an?elderly control group. We suggest that patients with PXE present vascular changes comparable with elderly patients and that these differences can not be explained by hypertension.     

Nephrogenic fibrosing dermopathy and calciphylaxis with pseudoxanthoma elasticum-like changes

Nephrogenic fibrosing dermopathy (NFD) and calciphylaxis are rare conditions that are associated with chronic kidney disease. Histopathologic changes, including dystrophic dermal calcification, often in association with elastic fibers have been observed in NFD and calciphylaxis. A pattern of dermal elastic fiber calcification that mimics pseudoxanthoma elasticum (PXE) has been previously reported as an incidental finding in the setting of calciphylaxis. Despite a shared association with renal disease and abnormal calcium deposits, however, NFD and calciphylaxis are discrete pathologic processes with distinct clinical and histopathologic features. Criteria for each are reviewed through case presentation of a patient meeting the clinical and histopathologic criteria for both NFD and calciphylaxis with histologic features mimicking PXE.     

Thick legs – not always lipedema

Due to its increased presence in the press and on television, the diagnosis of lipedema is on the way to becoming a trendy diagnosis for those with thick legs. Despite this, one must recognize that lipedema is a very rare disease. It is characterized by disproportional obesity of the extremities, especially in the region of the hip and the legs, hematoma development after minimal trauma, and increased pressure‐induced or spontaneous pain. Aids for making the correct diagnosis are (duplex) sonography, the waist‐hip index or the waist‐height index and lymphoscintigraphy. Important differential diagnoses are constitutional variability of the legs, lipohypertrophy in obesity, edema in immobility, edema in chronic venous insufficiency and rheumatic diseases. The symptom‐based therapy of lipedema consists of conservative (compression, manual lymphatic drainage, exercise) and surgical treatments (liposuction). Until now there is no curative therapy. Obesity is an important risk factor for the severity and prognosis of lipedema. Further studies for a better understanding of the pathogenesis of lipedema and in the end possible curative treatments are urgently needed.     

Adipose tissue remodeling in lipedema: adipocyte death and concurrent regeneration

Lipedema is a disease with unknown etiology presenting as bilateral and symmetric enlargement of the lower extremities due to subcutaneous deposition of the adipose tissue. Here we describe the histopathological features of the lipedema tissue and nonaffected adipose tissue obtained from a typical patient with severe lipedema. Immunohistochemical analyses indicated degenerative and regenerative changes of the lipedema tissue, characterized by crown-like structures (necrotizing adipocytes surrounded by infiltrating CD68+ macrophages; a feature commonly seen in obese adipose tissue) and proliferation of adipose-derived stem/progenitor/stromal cells (Ki67+CD34+ cells), respectively. These findings suggested increased adipogenesis in the lipedema tissue, which may further lead to hypoxia similar to that seen in obesity, resulting in adipocyte necrosis and macrophage recruitment. The confinement to the lower extremities and the difference from systemic obesity warrants further elucidation in future studies.     

Pseudoxanthoma elasticum with periumbilical perforation in a nullipara

Pseudoxanthoma elasticum (PXE) is an inherited multisystem disorder that primarily affects the skin and is characterized by progressive calcification and degeneration of the elastic fibers. PXE has recently been found to be caused by mutations in the ATP-binding cassette transporter C6 (ABCC6) or the multidrug resistance-associated protein 6 (MRP6) genes. Perforating PXE is a rare presentation that is usually seen in the periumbilical area in obese multiparous black women; it has distinct clinical and histopathological features and there may or may not be systemic manifestations. We report an unusual case of PXE in a nulliparous woman, with perforation in the periumbilical area and without any systemic involvement.     

Classic pseudoxanthoma elasticum in a girl with sickle cell disease

A pseudoxanthoma elasticum (PXE)–like phenotype develops in a subset of patients with inherited hemoglobinopathies. Although PXE tissue changes are thought to develop in the absence of ABCC6 mutations in patients with beta‐thalassemia, ABCC6 mutations have not been well evaluated among sickle cell disease patients with PXE‐like disease. To our knowledge, we describe the first patient with sickle cell disease, PXE skin findings, and two confirmed pathogenic ABCC6 mutations. This case suggests that ABCC6 testing is warranted for sickle cell disease patients with the PXE‐like phenotype and that the pathogenesis of PXE manifestations in beta‐thalassemia and sickle cell disease may differ.     

Pseudoxanthoma elasticum (PXE)-like calcification in adult dermatomyositis

A case of pseudoxanthoma elasticum (PXE)-like calcification in adult dermatomyositis (DM) is described. The patient was a 38-year-old woman with a history of dermatomyositis for 3 months. Yellowish, hard, papulo-plaque lesions, which looked like those of pseudoxanthoma elasticum, were noted on her left axilla. Calcium deposition was confirmed by X-ray, histopathological, and electron microscopic examinations. Histopathological and histochemical examinations showed acicular calcium deposition in the middle and deep dermis surrounded by mucin. Electron microscopic examination revealed that the calcium deposition was not on collagen fibers. These morphological features were distinct from those of PXE. We proposed the possibility that degenerated mucin or degenerated elastic fiber might result in subsequent calcium deposition in reticular calcinosis in adult DM. The calcification clinically disappeared without any specific treatment except for prednisolone and cyclophosphamide.     

S1 guidelines: Lipedema

The present, revised guidelines on lipedema were developed under the auspices of and funded by the German Society of Phlebology (DGP). The recommendations are based on a systematic literature search and the consensus of eight medical societies and working groups. The guidelines contain recommendations with respect to diagnosis and management of lipedema. The diagnosis is established on the basis of medical history and clinical findings. Characteristically, there is a localized, symmetrical increase in subcutaneous adipose tissue in arms and legs that is in marked disproportion to the trunk. Other findings include edema, easy bruising, and increased tenderness. Further diagnostic tests are usually reserved for special cases that require additional workup. Lipedema is a chronic, progressive disorder marked by the individual variability and unpredictability of its clinical course. Treatment consists of four therapeutic mainstays that should be combined as necessary and address current clinical symptoms: complex physical therapy (manual lymphatic drainage, compression therapy, exercise therapy, and skin care), liposuction and plastic surgery, diet, and physical activity, as well as psychotherapy if necessary. Surgical procedures are indicated if – despite thorough conservative treatment – symptoms persist, or if there is progression of clinical findings and/or symptoms. If present, morbid obesity should be therapeutically addressed prior to liposuction.     

Diffuse disease of elastic tissue and hyperphosphoremia

Pseudoxanthoma elasticum (PXE) is exceptionally associated with abnormal phosphate-calcium metabolism. On the other hand, significant hyperphosphataemia is present in tumoral calcinosis, with an occasional elastopathy resembling that of PXE. We report here the first case of diffuse elastic tissue disease associated with hyperphosphataemia in the absence of tumoral calcinosis. The patient, a 29-year old Gabonese, had severe arteritis of the lower limbs with linear calcifications of the aorta and major arteries of the limbs. Angioid streaks and calcifications were present in the retinas. The skin appeared to be normal, but histological examination of specimens from flexures showed abnormalities of the elastic tissue with many fibres being broken into small pieces and curled up. In a morphometric study of cutaneous elastic tissue these abnormalities were compared with those observed in a PXE patient and with normal elastic tissue. The abnormalities in our patient and in the PXE patient were similar. Compared to normal elastic tissue, there was a slight decrease in the total number of oxytalan and elaunin fibres. The elastic fibres were distinctly wider, longer and separated from each other by smaller spaces, but not more numerous than normally. The histopathological appearance of an artery removed during bypass surgery was similar to that of a PXE artery. The hyperphosphataemia was due to an increase in tubular absorption of phosphates without abnormalities of parathyroid hormone, or resistance to its phosphaturic effect or any other tubular disorder. It was little altered by aluminium carbonate, and it partially decreased after addition of calcitonin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pseudoxanthoma elasticum: evaluation of diagnostic criteria based on molecular data

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a genetic disorder due to mutations in the gene encoding the transmembrane transporter protein adenosine triphosphate binding cassette (ABC)-C6, resulting in calcification of elastic fibres in the skin, eyes and cardiovascular system. OBJECTIVES: To evaluate the diagnostic criteria for PXE based on molecular data. METHODS: Of 10 families with a positive history of PXE 142 subjects were investigated for clinical symptoms, histological findings and genetic haplotype analysis. RESULTS: Of these, 25 subjects were haplotypic homozygous for PXE and 23 had typical clinical and histopathological manifestations. Two of the 25 patients showed such marked solar elastosis and macular degeneration that PXE could not be confirmed clinically. Sixty-seven subjects were haplotypic heterozygous carriers and 50 were haplotypic homozygous unaffected. Of these 117 subjects, 116 showed no cutaneous or ophthalmological signs of PXE. In one of the 50 haplotypic homozygous unaffected patients important solar elastosis and scarring of the retina mimicked PXE lesions. Only four of the 67 haplotypic heterozygous carriers had biopsies of nonlesional skin; all were histopathologically normal. CONCLUSIONS: In our patients, PXE presents as an autosomal recessive genodermatosis. Correlation of haplotype and phenotype confirmed actual major diagnostic criteria. In patients with marked solar elastosis and/or severe macular degeneration clinical diagnosis can be impossible and molecular testing is needed to confirm the presence of PXE. To the best of our knowledge our large study compares for the first time clinical findings with molecular data.     

Pulmonary studies

The bulk of the evidence to date indicates that the lungs are spared in PXE. If there are rare cases of pulmonary alveolar (or vascular) elastic tissue calcification, future studies of autopsied cases should provide substantiating evidence for this contention. At present, Jackson and Loh's patient5 must be viewed as a complicated medical problem with other disorders beyond PXE that could have either accounted for in toto or at least contributed to his pulmonary calcification, which is well known to occur in many diseases unrelated to PXE.     

Histological skin changes in heterozygote carriers of mutations in ABCC6, the gene causing pseudoxanthoma elasticum

BACKGROUND: Pseudoxanthoma elasticum (PXE) is related to mutations in the ABCC6 gene and characterized pathologically by dystrophic and mineralized elastic fibres. Heterozygote carriers of ABCC6 mutations may have a limited PXE phenotype. OBJECTIVE: To compare histological changes in the skin of genotyped siblings from two PXE pedigrees. METHODS: Mutation analysis of ABCC6 was performed. Skin biopsy samples were stained (orcein) and immunolabelled for elastin, and for vitronectin and bone sialoprotein, which are partially responsible for the mineralization within the elastorrhexic fibres. Results In all individuals mutation analysis of ABCC6 allowed definition of the genotype status, i.e. PXE (n = 2), heterozygote (n = 7) or wild type (n = 2). The study identified three histological phenotypes related to the ABCC6 genotype in siblings from both families. Heterozygote carriers had changes in dermal elastic fibre organization, morphology and labelling midway between those seen in PXE skin and normal skin. CONCLUSION: Even though the number of individuals studied here is small and precludes any hasty generalization, having a single mutation in the ABCC6 gene seems enough to modify dermal elastic fibres. The relevance of performing a skin biopsy to identify heterozygote carriers in the family of a PXE patient remains to be determined.     

Pseudoxanthoma elasticum-like fibers in the inflamed skin of patients without pseudoxanthoma elasticum

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an inherited disorder leading to characteristic calcified elastic fibers in skin, eyes and vasculature. PXE-like fibers have not been described in inflammatory skin disease in the absence of other signs of PXE. METHODS: The histopathology of inflamed skin from 13 patients that contained PXE-like fibers but lacked clinical evidence of PXE were studied. Six of these and six comparison specimens from known patients with PXE were subjected to polymerase chain reaction amplification and sequencing of exons 24 and 28 of the PXE-associated gene ABCC6. This genetic analysis employed a novel assay utilizing paraffin-embedded tissue. RESULTS: Incidental PXE-like fibers were found in patients without clinical suspicion of PXE in lesional tissue showing lipodermatosclerosis, granuloma annulare, lichen sclerosus, morphea profunda, erythema nodosum, septal panniculitis, basal cell carcinoma and fibrosing dermatitis. Two patients with PXE-like fibers but without clinical findings of PXE were heterozygous for a PXE-associated ABCC6 sequence alteration. CONCLUSIONS: This pilot study shows elastic fibers similar to those of PXE in the lesional skin of patients with a variety of inflammatory skin diseases in the absence of clinical evidence of PXE; and some of these patients harbor changes in ABCC6.     

Elastosis perforans serpiginosa-like pseudoxanthoma elasticum in a child with severe Moya Moya disease

A 2-year-old girl with Moya Moya disease who had relapsing cerebrovascular strokes presented with loose skin folds, 'chicken' skin appearance and perforating elastosis serpiginosa-like lesions in the genitocrural region. Histologically, calcified material perforating the epidermis and adjacent short curled and mineralized elastic fibres suggested a variant of pseudoxanthoma elasticum (PXE). As PXE is known to be caused by various mutations in the transmembrane transporter ABCC6 gene, we hypothesized that a novel ABCC6 mutation may underlie this unique combination of PXE and elastopathic vascular damage. Therefore, the complete ABCC6 coding region of the patient and her parents was screened for genetic alterations. No bona fide disease-causing mutation of ABCC6 could be found in the child and in her parents. However, two novel allelic amino acid substitutions (Arg1273Lys and Glu1293Lys; exon 27) were found in the girl and her father, localized in close proximity to the region that codes for the functionally critical second nucleotide-binding fold of ABCC6. Although a causal involvement of these amino acid substitutions could not be proven based on this study, both heterozygote substitutions may possibly have interacted with other undetected recessive maternal ABCC6 changes in the child. To the best of our knowledge, this is the first report of an association between early-onset PXE and severe Moya Moya syndrome possibly related to ABCC6 changes.     

Pregnancy and obstetrical outcomes in pseudoxanthoma elasticum

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a genetic multisystem disorder characterized by calcified dystrophic elastic fibres in skin, retina and arteries. Much of the earlier literature on pregnancy in PXE contained reports of severe complications, leading some healthcare providers to advise women with PXE against becoming pregnant and some women with PXE to avoid pregnancy. OBJECTIVES: To evaluate the obstetrical outcomes and the incidence of pregnancy complications in women with PXE and to determine if pregnancy is associated with an adverse effect on the course of the disease. METHODS: Women with PXE (n = 407) answered detailed questionnaires regarding reproductive history and pregnancy as well as the course of their disease. The frequency of reported pregnancy outcomes and complications was determined. Severity indices for the major clinical manifestations of PXE were developed and correlated with gravidity of affected women aged 40 years or over. RESULTS: Among the 306 respondents with PXE who had ever been pregnant, there were 795 pregnancies. Of these, 83% ended in live births and 1% in stillbirth. The median birth weight was within the normal range and the incidence of low birth weight for gestation was low. Hypertension occurred in 10% of pregnancies, gastric bleeding and retinal complications in < 1%, and 12% of pregnancies were associated with worsening of skin manifestations. There was no effect of gravidity and clinical severity on cutaneous (P = 0.07), ocular (P = 0.59) or cardiac (P = 0.42) manifestations of PXE in women aged 40+ years, nor did ever having been pregnant adversely affect these clinical severity indices. Of the 101 women who had never been pregnant, 17% made the decision because they were advised against becoming pregnant by a healthcare professional and 11% did not become pregnant because they feared an adverse outcome either in their pregnancy or disease. CONCLUSIONS: PXE is not associated with markedly increased fetal loss or adverse reproductive outcomes. The incidence of gastric bleeding, although probably higher than in the unaffected population, is much lower than previously reported, and retinal complications are uncommon. Although a few pregnancies were associated with worsening of skin manifestations, there was no correlation of either gravidity or ever having been pregnant with ultimate severity of skin, ocular or cardiovascular manifestations. There is no basis for advising women with PXE to avoid becoming pregnant, and most pregnancies in PXE are uncomplicated.     

Mammographic findings in pseudoxanthoma elasticum

BACKGROUND: There have been isolated case reports of arterial and skin calcification in mammograms of patients with pseudoxanthoma elasticum (PXE), and unpublished anecdotes of many women with PXE undergoing breast biopsy for evaluation of microcalcifications. OBJECTIVE: Our aim was to systematically evaluate mammography and breast pathology in PXE. METHODS: The mammograms of 51 women with confirmed PXE were compared with those of a control sample of 109 women without PXE, noting each of the following characteristics on each mammogram: breast density, skin thickening, skin microcalcifications, vascular calcification, breast microcalcifications and macrocalcifications, and masses. The characteristics of the 2 samples were compared using the 2-tailed t test with a pooled estimate of variance. The indications for mammography and data for each of the mammographic findings were analyzed using the chi(2) test. Available breast biopsy material was reviewed. RESULTS: The PXE and control groups were similar in age and indications for mammography. There was a statistically significant increase in skin thickening, vascular calcification, and breast microcalcifications in the PXE group (P <.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 <.001). Nearly 1 in 7 of the patients with PXE demonstrated at least 3 of the following: microcalcifications, skin calcifications, vascular calcification, and skin thickening; whereas 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. CONCLUSION: Breast microcalcification and arterial calcification are not rare in the normal population and are not of diagnostic value. 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.     

Neuropsychologic studies

Although a full spectrum of neurologic and psychiatric symptoms and disorders has been reported in PXE patients, the overall incidence appears to be low.Cerebrovascular calcification has been commonly observed by angiographie methods. This should provide a basis for symptoms related to vascular ischemia, total occlusion, or frank hemorrhage, yet not a single patient in the present group had experienced a major stroke (one patient had a ruptured cerebral aneurysm). The possibility of minor strokes (or transient ischemie attacks) causing organic brain damage was investigated through neuropsychologic testing of 27 patients from the group and showed only questionably positive results to suggest that the PXE group suffered from organic brain damage more than age-and sex-matched controls.Emotional lability and neurotic tendencies have been reported by others to occur in up to 5% of the PXE population, but, again, neuropsychological testing failed to elicit even this low a figure, indicating that while such manifestations may be associated with PXE, an increased incidence compared with the general population is slight to nil.Because rare examples of all types of cerebrovascular accidents have been reported in PXE, with extremely rare cases occurring at an early age, this possibility must be kept in mind. Therefore, any patient with PXE exhibiting neurologic or psychologic symptoms or signs should be considered to be experiencing complications of PXE until proven otherwise.     

Hyperimmunoglobulin E syndrome

A 24-year old woman had the major features of the hyperimmunoglobulin E syndrome: recurrent staphylococcal skin infections (from the age of 6 months), an extremely elevated serum immunoglobulin E level (25,000 units/ml), and defective neutrophil chemotaxis. This patient also had peripheral blood eosinophilia and cutaneous candidiasis. There was a family history of asthma, but the patient herself did not have a history of asthma or hay fever, and, on examination, had no evidence of atopic dermatitis. The patient has not had any systemic infections. Results of the skin biopsy showed dermal edema and a perivascular infiltrate with eosinophils and an increased number of mast cells. The clinical spectrum of the hyperimmunoglobulin E syndrome may include atopic dermatitis, mucocutaneous candidiasis, systemic infections, and/or the features of Job's syndrome.