Acquired hyalinosis cutis et mucosae in plasmacytoma with monoclonal IgG-lambda gammopathy

A 66-year-old female patient developed within 2 years clinical symptoms of hyalinosis cutis et mucosae due to a plasmocytoma with monoclonal IgG-light-chain gammopathy. The clinical diagnosis was supported by light- and electron-microscope studies. The form of hyalinosis cutis et mucosae described by Urbach and Wiethe is a genetic disease with its onset in early childhood. For this reason, we propose the designation "acquired hyalinosis cutis et mucosae" for the case reported here.     

Hyalinosis cutis et mucosae: a 30 year follow up of a female patient

Hyalinosis cutis et mucosae is an inherited disease, characterized by deposition of a hyaline-like substance in the dermis and internal organs. In the present study, we report a 30 year follow up in a female patient with hyalinosis cutis et mucosae treated using dermabrasion and oral retinoids. In our opinion, the lesion on uncovered body areas should be corrected as soon as possible to enable a normal psychophysical development. The lesions on skin and oral mucosa may be successfully removed without remission with dermabrasion in early childhood. In addition, oral retinoids in adulthood may produce some improvement.     

Hyalinosis cutis et mucosae (Urbach-Wiethe) in 2 sisters

The authors report on 2 sisters who had suffered from both atopic eczema and hoarseness since their birth. Rough, yellowish-white papular deposits in the skin and the oral mucosa had developed during their childhood. The clinical diagnosis of hyalinosis cutis et mucosae was confirmed in both cases by means of histology and electron microscopy.     

Hyalinosis cutis et mucosae (Urbach-Wiethe disease)--ultrastructural and immunological characteristics

In this report on a young female patient with hyalinosis cutis et mucosae (Urbach-Wiethe disease, lipoid proteinosis), we present the clinical, immunological and ultrastructural features of this inherited disorder and discuss the differential diagnosis against other interstitial connective tissue depositions. Immunologically, the most important result was the increased amount of collagen type IV at the junction zones of epidermis, dermal vessels and appendages. This was in accordance with the ultrastructural deposition of hyalin material, mainly consisting of multiplied basal laminae at the respective junction zones. The pathogenesis (gene defect or defective gene regulation?) and therapy are discussed.     

Late onset hyalinosis cutis et mucosae

Two cases of non-familial, late onset (50 and 62-years-old) hyalinosis cutis et mucosae were studied and compared with classical early onset cases. Late onset cases showed essentially the same histological and ultrastructural features described for early onset cases. The late onset variety should be distinguished from other diseases; they resemble systemic amyloidosis and sometimes the adult form of colloid milium.     

Corrective dermatosurgery in childhood--own experience

Congenital and acquired lesions on children's skin impose great burden upon the children and their parents. These children are frequently faced with various kinds of embarrassment in communication with their peers, ranging from sneering and mockery to isolation. That is why these lesions, especially if readily observable, should be completely removed or at least corrected as soon as possible to enable the child to establish normal communication with the environment and to prevent psychic trauma that may entail serious consequences later in life. Seven pediatric patients burdened with such lesions are presented (naevus papillomatous et verrucosus colli, atrophia linearis cutis faciei, naevus hyperkeratoticus systemicus dorsi, ichthyosis nigra, poikiloderma congenitum, hyalinosis cutis et mucosae, and alopecia post combustionem). Dermabrasion was used in six patients, whereas occipital hair graft transplantation to the alopecic sites was used in a girl with posttraumatic alopecia.     

Clinical and molecular abnormalities in lipoid proteinosis

Lipoid proteinosis (hyalinosis cutis et mucosae) is a rare, autosomal recessive disease. The main clinicopathological features comprise skin and mucous membrane infiltration and scarring with deposition of hyaline material. In this report, we describe a 6-year-old boy in whom a diagnosis of lipoid proteinosis was first suspected when he presented with blisters and erosions at 4 years, a history of life-long dysphonia and a previous epileptic convulsion. The diagnosis was confirmed by histology and identification of a homozygous frameshift mutation, 501insC, in exon 6 of the gene encoding extracellular matrix protein 1, ECM1. Lipoid proteinosis may show protean clinical features and be difficult to diagnose on clinical grounds alone. This case report illustrates that lipoid proteinosis may show protean clinical features and yet remain undiagnosed for many years. Although the gold standard for definite diagnosis remains histology, molecular characterisation of the gene mutation will add to our understanding of genotype-phenotype correlation and perhaps to the development of a rationale for future therapeutics.     

Elektronenmikroskopische Befunde des Hyalins bei Hyalinosis cutis et mucosae. Gleichzeitig ein Beitrag zur Frage der Entstehung des Hyalins

Zusammenfassung Bei einem Kranken mit Hyalinosis cutis et mucosae wurde das Hyalin elektronenmikroskopisch untersucht. Es läßt sich als ein nicht orientiertes Flechtwerk feiner Filamente in breiten mantelartigen Schalen um Gefäße darstellen. Die Basalmembran ist lamellär einbezogen. Einzelne kollagene Fasern finden sich im Hyalin eingebaut. Es bestehen räumliche Beziehungen zu Fibroblasten.In Analogie zu neueren pathogenetischen Vorstellungen beim Amyloid wird auch beim Hyalin die primäre Veränderung am Ort der Ablagerung selbst vermutet und die Transsudation von Plasmaeiweißen als sekundär und fakultativ im Sinne des Schlammfangs gedeutet.

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Electron microscopic investigation of hyaline in hyalinosis cutis et mucosae (lipoid-proteinosis urbach-wiethe)

Summary Electron microscopic investigation of hyaline in a patient with lipoid-proteinosis (Urbach-Wiethe) revealed a non-orientated network of thin filaments broadly coating the blood vessels and including the laminated basal membrane. Isolated collagen-fibrils were found in the hyaline. Spatial connection to fibroblasts could be detected.In analogy to more recent views about the pathogenesis of amyloid it is suggested that in hyalinosis, too, the primary changes seem to be located at the side of the deposits and transsudation of plasma-proteins is secondary and facultative.

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Herrn Prof. Dr. J. Tappeiner zum 60. Geburtstag gewidmet.     

The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1

Lipoid proteinosis (OMIM 247100), also known as Urbach-Wiethe disease or hyalinosis cutis et mucosae, is a rare autosomal recessive disorder characterized by generalized thickening and scarring of the skin and mucosae. In 2002, the disorder was mapped to a locus on chromosome 1q21 and pathogenic mutations were identified in the ECM1 gene, which encodes for the glycoprotein extracellular matrix protein 1 (ECM1). ECM1 has since been shown to have several important biological functions. It has a role in the structural organization of the dermis (binding to perlecan, matrix metalloproteinase-9 and fibulin) as well as being targeted as an autoantigen in the acquired disease lichen sclerosus. ECM1 also shows over-expression in certain malignancies and is abnormally expressed in chronologically aged and photo-aged skin. Thus far, 26 different inherited mutations in ECM1 have been reported in lipoid proteinosis. In this article, we provide an update on the molecular pathology of lipoid proteinosis, including the addition of 15 new mutations in ECM1 to the mutation database, and review the biological functions of the ECM1 protein in health and disease.     

Ultrastructure and composition of connective tissue in hyalinosis cutis et mucosae skin

Skin biopsies from a patient with hyalinosis cutis et mucosae (HCM) were studied by routine histology, electron microscopy, biochemical extractions, and immunofluorescence for extracellular matrix proteins. The upper dermis consisted of large hyaline regions mainly composed of noncollagenous proteins. A portion of this material was solubilized by reduction in 8 M urea. Anti-sera against these proteins revealed multiple antigens most of which were also detectable in normal skin. The hyaline regions showed a reduced content of collagens, particularly of thick fibrils and of fibronectin. The basal lamina around capillaries and at the dermal-epidermal junction appeared as multiple, concentric layers of amorphous laminae intercalated with thin collagen fibrils. They consisted of collagens type III and IV and of laminin as shown by immunofluorescence. Antibodies could also be raised against laminin of HCM skin which showed strong cross-reactions with authentic mouse laminin. Cultured fibroblasts from the HCM lesion showed increased synthesis of noncollagenous proteins at the expense of newly synthesized collagens. Some but not all of these noncollagenous proteins were also produced by fibroblasts from normal skin. The above data indicate that the hyaline material in HCM originates from the overproduction of noncollagenous proteins, most of which are normal constituents of human skin.     

HISTOGENESIS OF HYALINOSIS CUTIS ET MUCOSAE

Light microscopically, reticulum fibers and argyrophilic materials were found by reticulum staining, and lipid droplets by Sudan III staining, around the blood vessels and in the interstices of the smooth muscle fibers of tunica dartos; toluidine blue staining of thick sections of Epon-embedded tissue revealed poorly-stained, glass-like, amorphous hyalin with configuration of collagen fibers in the same areas and hyalinized muscle fibers in tunica dartos. Electron microscopy disclosed that multiplication of the basal lamina and its transition to the fibrogranular amorphous material, probably a hyalin substance, was seen around the true smooth muscle cells of tunica dartos and also around the blood vessels. In addition, dilated rough-surfaced endoplasmic reticulums with fibrogranular content were often observed in the endothelial cells, pericytes, and smooth muscle cells, with Golgi apparatus in some parts. These findings suggest that hyalinosis cutis et mucosae is due to the accumulation and invasion of hyalin into the normal collagen fibers due to a genetic abnormality in the synthetic processes of smooth muscle cells, vascular endothelial cells, pericytes and some fibroblast-like connective tissue cells. In my speculation, the hyalin substance in this disease may be normal collagen invaded by basal lamina glycoprotein, most probably involving type III and/or type IV collagen.     

An unusual adverse effect of nadroparin injections: Calcinosis cutis

In 1988, Tumiati et al described the first case of calcinosis cutis related to a calcium-containing heparin. Since then, only 18 cases have been reported in the literature; they usually have an altered calcium-phosphate product, an elevated parathyroid hormone (PTH), or both. We report a 33-year-old patient who developed calcinosis cutis at sites of nadroparin injections without any disturbance of calcium-phosphate product, PTH, or vitamin D. The pathogenesis of calcinosis cutis secondary to nadroparin injections remains controversial; Proposed causes included metastatic, dystrophic, iatrogenic, or multifactorial etiologies. This is the first case of multiple nodules of calcinosis cutis without alterations of calcium-phosphate product, PTH, or vitamin D, which supports an iatrogenic mechanism. We also suggest that calcinosis cutis could be more frequent than we thought and is probably an underdiagnosed entity.     

Selected disorders of connective tissue: pseudoxanthoma elasticum, cutis laxa, and lipoid proteinosis

There has been progress made in the understanding of 3 Mendelian disorders: pseudoxanthoma elasticum, cutis laxa, and lipoid proteinosis cutis and mucosae. While they are primary connective tissue diseases, their names imply a connection to the skin, and in fact, it is often the dermatologist who makes the diagnosis. It seems rational that defects in various extracellular matrix proteins cause lipoid proteinosis or subtypes of cutis laxa, yet the discovery of a liver- and kidney-based transmembrane transporter as the culprit of pseudoxanthoma elasticum was rather surprising and may shed new light on elastic tissue homeostasis.     

Junctional basement membrane anomalies of skin and mucosa in lipoid proteinosis (hyalinosis cutis et mucosae)

BACKGROUND: Excessive basement membrane (BM) deposition in skin and mucosa is characteristic for lipoid proteinosis (LP; hyalinosis cutis et mucosae), an inherited disease caused by extracellular matrix protein 1 (ECM1) mutations. According to ultrastructure there are striking differences between junctional and microvascular BM. OBJECTIVE: Distinct analysis of the junctional zone in epidermis and oral mucosa, contrasting concentric BM arrays in the microvasculature; evaluation of impact on epithelial histogenesis and differentiation, and specifically on adhesion structures to BM (hemidesmosomes). METHODS: LP-epithelia were analyzed for alterations in differentiation, BM composition and texture, and hemidesmosomal components by indirect immunofluorescence (IIF), electron microscopy (EM), and immunoelectron microscopy (ImEM). RESULTS: Most striking was the irregular deposition of collagen IV and VII, BM-laminin, and laminin-5 at the junctional zone, accompanied by lamellate or punctuated structures below BM (IIF), whereas integrin alpha6beta4 and bullous pemphigoid antigen-1 and -2 (BPAG-1/-2) were regularly aligned. Also integrins alpha2beta1 and alpha3beta1 remained restricted to the epidermal basal layer, while the tissue-specific differentiation markers keratin K1/10 (mucosa, additionally K4/13) appeared delayed indicating mild hyperplasia, further confirmed by focal K6/16 expression. Ultrastructure (EM) disclosed abundance of extended basal cell protrusions and junctional aberrations like exfoliating excessive BM material. Hemidesmosomes were complete, but ImEM indicated weakened interactions between their components (BPAG-1, -2, and HD1). Confirming IIF, collagen IV and VII, and laminin-5 appeared extensively scattered, the latter two probably remaining associated. CONCLUSIONS: Subtle defects in anchorage assembly, spanning the entire BM zone, apparently compromise epithelial-matrix adhesion, which may provoke (mechanical stress-induced) erroneous BM repair.     

Hyalinosis cutis et mucosae

Hyalinosis cutis et mucosae is a rare autosomal recessive disorder which is characterized by deposition of hyaline material around the basement membrane of the skin and mucous membranes. Typical clinical symptoms are hoarseness, infiltration of the mucous membranes and papular verrucous skin changes. Mutations within the extracellular matrix protein gene (ECM‐1) are the underlying defect.We report on a 24‐year‐old man, who had first been seen inour department at the age of seven and had undergone the necessary diagnostic procedures and who revisited 17 years later with hoarseness and extensive verrucous skin changes at elbows and knees which were removed by excision. A new mutation of the ECM1 gene was identified.     

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.     

Cutis laxa in a patient with 1p36 deletion syndrome

Chromosome 1p36 deletion is the most common subtelomeric deletion syndrome characterized by variable features including unique facial appearance, intellectual disability, developmental delay, cardiac defects, seizures and hypotonia. Here, we report a patient with developmental delay, dilated cardiomyopathy, seizures, hirsutism and cutis laxa who was diagnosed with 1p36 deletion syndrome by chromosome microarray analysis. This patient is the first reported case of 1p36 deletion syndrome associated with cutis laxa and our results suggest that the 1p36 region contains one or more genes relevant to cutis laxa. This case also indicates the importance of considering chromosome abnormalities (microdeletion/microduplication syndromes) in patients presenting skin disorders combined with unexplained developmental delay, intellectual disability or multiple congenital abnormalities.     

Beitrag zur Klinik und Pathogenese der Hyalinosis cutis et mucosae (Lipoid-Proteinose Urbach-Wiethe)

Zusammenfassung 1. Es werden 3 Fälle von Hyalinosis cutis et mucosae (Lipoid-Proteinose Urbach-Wiethe) beschrieben.2. Bei einem dieser Patienten finden sich intrakranielle Verkalkungen, die in Verbindung mit epileptischen Anfällen und einer gewissen Debilität auf eine Miterkrankung des Gehirnes hinweisen.3. Aus dem familiären Auftreten und der deutlichen Häufung von Blutsverwandtschaft bei den Eltern läßt sich auf einen recessiven Erbgang schließen.4. Die histologischen und histochemischen Untersuchungen sowie Fettanalysen im Gewebe und Blut machen die Annahme, daß es sich bei der Hyalinosis cutis et mucosae um eine Fettstoffwechselstörung (phosphatidige Lipoidose Urbach) handelt, wenig wahrscheinlich. Eher wäre auf Grund des histologischen Bildes und der elektrophoretisch nachgewiesenen Verschiebungen der Eiweißzusammensetzung des Serums an eine Eiweißstoffwechselstörung zu denken, vielleicht im Zusammenhang mit einer endokrinen Dysregulation. Diese Annahme schließt nicht aus, daß eine Störung der terminalen Strombahn an der Entstehung und der Lokalisation dieses Krankheitsbildes mitbeteiligt ist.Mit 20 Textabbildungen.Herrn Prof. A. Stühmer zu seinem 65. Geburtstage gewidmet.     

Aleukemic leukemia cutis presenting as benign-appearing exanthema.

Aleukemic leukemia cutis is a rare condition characterized by the infiltration of the skin by leukemic cells before their appearance in the peripheral blood or bone marrow. We report here a 62-year-old seemingly healthy patient who presented with disseminated erythematous maculae. A skin biopsy showed leukemia cutis of monocytic type. No involvement of bone marrow or peripheral blood was found. The patient developed acute monocytic leukemia 7 months later. We present this case to illustrate how leukemia cutis can masquerade as a clinically benign-appearing cutaneous eruption without leukemic changes in blood or bone marrow. To confirm the diagnosis of aleukemic leukemia cutis, immunohistochemistry of the skin lesions as well as a complete staging procedure is necessary.