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failure of mucocutaneous lymphangiogenesis may underlie the clinical
features of lipoid proteinosis.Br
J Dermatol. 2007 Jan;156(1):152-7
Lipoid
proteinosis (LiP) (OMIM 247100) is a rare autosomal recessive disease
caused by loss of function mutations in the extracellular matrix
protein 1 gene, ECM1, on chromosome 1q21. LiP is characterized
clinically by hoarseness in early infancy, followed by waxy papules
and plaques on the face and body along with pox-like and acneiform
scars. We studied a 20-year-old Japanese woman with LiP. She was born
of consanguineous parents. Biopsy specimens obtained from a nodule on
the elbow were used for histopathology, immunohistology and electron
microscopy. Exons 6 and 7 of ECM1 were amplified by polymerase chain
reaction (PCR) from genomic DNA from the proband, her parents, her
brother and an unrelated person. PCR products were sequenced to detect
the mutation. Histopathological examination revealed an irregular mass
of calcium beneath deposits of a hyaline material in the dermis.
Immunofluorescence double staining showed that the CD31-positive
microvascular density was increased but that staining for the
lymphatic-specific hyaluronan receptor LYVE-1 was drastically
diminished in lesional compared with nonlesional skin of the patient
and with normal skin. Electron microscopy revealed marked concentric
reduplication of basal laminae not only around blood vessels but also
around solitary dermal cells positive for Weibel-Palade bodies
scattered in the hyaline material. Sequencing of the PCR products
revealed a homozygous frameshift mutation, 507delT, in exon 6. This
led to a premature stop codon 23 bp downstream. The results of
immunopathological and ultrastructural characterization suggest that a
failure of mucocutaneous lymphangiogenesis may underlie the clinical
features of LiP. Identification of mutation 507delT in a Japanese
patient with LiP further supports the thesis that this mutation
represents a recurrent mutation in ECM1 in patients with LiP. To our
knowledge, this case represents the first report of calcinosis cutis
occurring in LiP.
Junctional
basement membrane anomalies of skin and mucosa in lipoid proteinosis (hyalinosis
cutis et mucosae).J
Dermatol Sci. 2007 Mar;45(3):175-185.
Epub 2006 Dec 15.
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.
Lipoid proteinosis:
case report and review of the literature.
Acta Otorhinolaryngol Ital. 2006 Jun;26(3):162-7.
Lipoid
proteinosis is a rare autosomal recessive disorder, characterized
histologically by infiltration of periodic acid Schiff-positive
hyaline material into the skin, upper aerodigestive tract, and
internal organs. Classical clinical features include skin scarring,
beaded eyelid papules, and laryngeal infiltration leading to
hoarseness. Moreover, the infiltrates in the tongue and its frenulum
limit lingual movements and cause speech difficulties. Usually, the
hoarse voice is present at birth or in early infancy, as the first
manifestation. In more severe cases, diffuse infiltration of the
pharynx and larynx might cause respiratory distress, at times
requiring tracheostomy. The disorder has recently been shown to result
from loss-of-function mutations in the extracellular matrix protein 1
gene on chromosome 1q21. The function of the protein extracellular
matrix protein 1 gene is still unclear, although an important role in
skin physiology and homeostasis has been hypothesized. In this report,
the case is described of a 6-year-old girl with lipoid proteinosis.
Histopathological examination of a laryngeal biopsy specimen showed
massive deposits of eosinophilic, periodic acid Schiff-positive, and
diastase resistant material in the lamina propria corroborating the
clinical diagnosis of lipoid proteinosis. Molecular analyses in this
patient also confirmed the clinical diagnosis. The proposita was a
compound heterozygote for a new small rearrangement (543de1TG/ins15)
in exon 6, and a nonsense mutation (Arg243Stop) in exon 7. Together
with previously documented mutations in the extracellular matrix
protein 1 gene, this study supports the hypothesis that exons 6 and 7
are the most common sites for extracellular matrix protein 1 gene
mutations in lipoid proteinosis.
OC12
Lipoid proteinosis (Urbach-Wiethe disease).Oral
Dis. 2006 Sep;12(s1):12.
Lipoid
proteinosis (LP), also known as Urbach-Wiethe disease is a rare,
autosomal recessive disorder associated with deposition of acid-Schiff
(PAS)-positive hyaline-like material in various tissues including
skin, mucosal membranes and internal organs. The aetiology of LP is
currently unknown. A 17-year-old male complaining of oral lesions and
tooth pain was referred to our clinic, depending on characteristic
infandible hoarseness, pox-like and acneiform scar-like lesions on his
face, beaded eyelid papules, loss of hair, tuberous nodules on the
elbows and generalized skin thickening had been diagnosed with LP. He
had the characteristic old-looking appearance. Intraoral examination
showed macroglossia with a thickened frenulum and lateral impressions
of teeth, yellowish papules on the tongue and yellowish deposits on
the soft palate. There wasn't any structural abnormalities in
radiographic examination. He had no other systemic disorder. He had
poor oral hygiene, severe periodontal problems and multiple severe
caries lesions. The patient was evaluated for the individual treatment
needs of the problems he had been. The teeth extractions, restorative
and periodontal treatments were done. Intraoral tissues were fragile,
and healing process was observed to be slower than usual. In this
case, limited mouth opening, macroglossia and the thickened oral
mucosa restricted the treatment procedures in oral region. Throughout
medical treatment patient's oral health status will be followed. This
report pointed out to the rare finding of gingival hyperplasia due to
hyalin-like material deposition in gingival tissues, which was not
induced by any drug therapy.
Ophthalmic
manifestations of lipoid proteinosis.Presse
Med. 2006 May;35(5 Pt 1):796-8.
INTRODUCTION:
Lipoid proteinosis (LP), also known as hyalinosis (or lipoidosis)
cutis et mucosae or Urbach-Wiethe disease, is a rare autosomal
recessive disorder. It is associated with deposits of protein-lipid
complexes in various tissues including the skin and mucous membranes.
Ophthalmologic manifestations are frequent and can affect visual
prognosis. CASE: This 28-year-old patient presented vesiculobullous
lesions of the face that developed into varioloid scars associated
with hoarseness. Ophthalmologic examination revealed unilateral
lesions including hyaline deposits on the palpebral margins, iris, and
trabecular zone, complicated by uveitis, cataract, and glaucoma, which
caused the functional loss of the left eye. Histological examination
of a cutaneous biopsy confirmed the diagnosis. DISCUSSION: Involvement
of the eyelids is characteristic, and moniliform blepharosis is
pathognomonic and frequent. This case featured a rare intraocular form
(uveitis). Deposits may be found on the conjunctiva, cornea, trabecula
and Bruch membrane. Conjunctival or cutaneous biopsy confirms the
diagnosis. Available treatment is quite limited.
Lipoid
proteinosis: report of three familial cases.Dermatol
Online J. 2006 Jan 27;12(1):16
Lipoid
proteinosis is a rare autosomal recessive disorder; it presents in
early childhood with hoarseness, skin infiltration and thickening with
beaded papules on eyelid margins, and facial acneiform or pock-like
scars. Although 250 cases have been reported until now, the occurrence
of disease in siblings is very rare. We report three familial cases of
lipoid proteinosis involving a brother and sister and their nephew.
Lipoid
proteinosis in a 12-year-old child: a report from west India.
Dermatol Online J. 2006 Jan 27;12(1):10
A 12-year-old
male child born of non-consanguineous parents presented with multiple
skin lesions, hoarseness of voice, and episodes of epilepsy since
early childhood. The findings of characteristic beaded eyelid margins,
patchy alopecia of the scalp, hoarseness of voice, and epilepsy were
consistent with a rare clinical diagnosis, lipoid proteinosis. Skin
biopsies obtained from representative skin lesions were subjected to
histology and electron microscopy. Light microscopy demonstrated
PAS-positive diastase-resistant material in the papillary dermis of
skin. Ultrastructure revealed granulo-filamentary aspect of the
accumulated material. Although this rare autosomal recessive disorder
has been described in the literature, its occurrence is rare in India.
Vascular
anomalies in lipoid proteinosis (hyalinosis cutis et mucosae):
basement membrane components and ultrastructure.J
Dermatol Sci. 2006 Jun;42(3):231-9. Epub
2006 Feb 21
BACKGROUND: In
lipoid proteinosis (LP) vascular anomalies represent severe functional
defects caused by excessive deposition of basement membrane (BM)-like
matrix, particularly around small subepithelial blood vessels.
OBJECTIVE: Correlation of microvascular anomalies in morphology and
ultrastructure with extracellular matrix composition and cell
interactions for elucidating vascular involvement in LP-pathophysiology.
METHODS: Biopsies from non-related LP-patients were analyzed by
indirect immunofluorescence (IIF), electron microscopy (EM), and
immune-EM (ImEM). RESULTS: In LP-skin and mucosa the thickened vessel
walls stained strongly for the BM-components type IV collagen, laminin,
perlecan, and nidogen (IIF). Integrin alpha6beta4 was regularly
collocated with endothelial surface markers such as PECAM (CD31).
Ultrastructure (EM) revealed highly ordered matrix deposits around
microvessels, with frequently collapsed lumina, functionally
compensated by increased vascular density (histology, IIF). Pericytes
were trapped between these concentric BM-layers at varying distances
towards the periphery (EM), contrasting their regularly close
endothelial apposition. Periodic type IV collagen patterns (ImEM)
corroborated the multiple BM-leaflet structure and the lack of a
common 'fused' endothelial-pericyte BM, seen normally. Presumptive
secretory vesicles, abundant in both cell types, implied an equal
contribution to BM-synthesis, but also indicated partial loss of
endothelial polarity. CONCLUSIONS: In LP thickened vessel walls,
composed of multiple BM, profoundly alter microvascular properties,
also by interference with endothelial-pericyte interactions. The
increased microvascular density reflects compensatory restoration for
disabled function. Most remarkable was the exaggerated secretory
activity (also at luminal surfaces) underlining the regulatory key
role of extracellular matrix protein 1 (ECM1; mutated in LP) in export
or turnover of all major BM-components.
Lipoid
proteinosis.Actas
Dermosifiliogr. 2005 Apr;96(3):164-6
Lipoid
proteinosis is an infrequent disease characterized by the deposition
of a PAS-positive diastase-resistant hyaline material in the skin and
respiratory tract, although it can also be deposited in internal
organs, in a generally asymptomatic manner. The earliest clinical
manifestation is hoarseness. Clinical cutaneous manifestations come
later, in the form of hyperkeratotic lesions located on the trunk,
elbows, axillae, groins, backs of hands, palms and soles. A lesion
typical of the disease is moniliform blepharosis, which consists of
beaded papules along the eyelid margins. Also characteristic is the
presence of comma-shaped intracranial calcifications in the temporal
lobes. The course of the disease is progressive, with a normal life
expectancy. It affects men and women equally, with worldwide
distribution. The diagnosis is based on the clinical symptoms and the
histology. At this time, there is no effective treatment for the
disease. We present a case of lipoid proteinosis in a 23-year-old
woman, with typical clinical and histological characteristics.
Clinical
and molecular abnormalities in lipoid proteinosis.Eur
J Dermatol. 2005 Sep-Oct;15(5):344-6
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.
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