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Clinical and molecular abnormalities in lipoid proteinosis

European Journal of Dermatology. Volume 15, Number 5, 344-6, September-October 2005, Genes and skin

Summary

Author(s) : S Desmet, SA Devos, I Chan, T Hamada, I Dhooge, JA Mcgrath, JM Naeyaert , Department of Dermatology, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, BelgiumFax: (+32)-9-240 49 96., Genetic Skin Disease Group, St John’s Institute of Dermatology, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK, Department of ENT, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.

Summary : 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.

Keywords : extracellular matrix protein 1 gene (ECM1), genodermatosis, hyalinosis cutis et mucosae, Urbach-Wiethe disease

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ARTICLE

Auteur(s) : S Desmet¹, SA Devos¹, I Chan², T Hamada², I Dhooge³, JA Mcgrath², JM Naeyaert¹

¹Department of Dermatology, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, BelgiumFax: (+32)-9-240 49 96.
²Genetic Skin Disease Group, St John’s Institute of Dermatology, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK
³Department of ENT, Ghent University Hospital, De Pintelaan 185, B-9000 Gent, Belgium

accepté le 25 Mai 2005

Lipoid proteinosis (LP), also referred to as hyalinosis cutis et mucosae or Urbach-Wiethe disease, was first described in 1929 by Urbach, a dermatologist, and Wiethe, an otolaryngologist [1]. This rare, autosomal recessive disorder is characterized by hyaline deposits in the skin, mouth and upper respiratory tract, and other internal organs [2-4]. Hoarseness due to vocal cord infiltration is usually the first symptom and, in most cases, appears during infancy [5]. Characteristic “beaded” papules, known as moniliform blepharosis, may be present along the margins of the upper and lower eyelids [6]. Verrucous lesions may occur on the extensor surfaces of the limbs, especially the elbows and the hands, mostly after friction or trauma [5]. Dental abnormalities, alopecia, intracranial calcification and epilepsy are also recognised clinicopathological features of lipoid proteinosis [7]. The prognosis of lipoid proteinosis is usually good, although respiratory tract obstruction is a frequent complication [6, 8]. Histologically, LP is characterized by deposition of hyaline material in the dermis, surrounding blood vessels and adnexial epithelia and basement membrane thickening at the dermal-epidermal junction [6].In this report, we describe a 6-year-old Belgian boy with lipoid proteinosis. This case illustrates the fact that a high index of suspicion is required to diagnose LP when the characteristic moniliform blepharosis and verrucous lesions have not yet developed. Indeed, in this boy the clinical presentation was dominated by the presence of recurrent blisters, erosions, scarring and impetigo-like lesions. A pathogenic loss-of-function mutation in the extracellular matrix protein 1 gene (ECM1) was demonstrated in this patient [9].

Case report

The patient was a 6-year-old boy, born of non-consanguineous parents, and with no history of other affected family members. He presented at the age of 4 years with recurrent super-infected erosions and blisters. These had been present for over 2 years, and mainly affected the head and neck. Scars were noted at sites of previous blistering. Previous diagnosis included cutaneous porphyria and even battered child. Skin examination revealed multiple atrophic scars on the trunk, face and neck (( figure 1 )). Notably, his facial skin had a remarkable waxy texture. Somewhat infiltrated plaques were seen on the elbows, wrists and the knees, as were ecchymoses and crusts on the extremities (( figure 2 )). He also had a history of an epileptic convulsion (grand mal and temporal lobe features) aged 3 years, following which he was prescribed oral carbamazepine. In addition, he had a life-long history of dysphonia, typified by alternating whispering and hoarseness. Laryngoscopy revealed thickening of the vocal cords and a cobblestone appearance to the whole trachea. Laboratory findings, including a porphyrin screen, were normal. The clinical features were highly suggestive of lipoid proteinosis. The diagnosis was confirmed by a biopsy, taken from infiltrated mucosa from the lower lip. It showed a deposition of pale, eosinophilic, hyaline material in the thickened superficial dermis, around small blood vessels and at adnexial epithelia (( figure 3 )). The hyaline material stains strongly with PAS (( figure 3 )). Direct sequencing of lymphocyte-derived genomic DNA for the extracellular matrix protein 1 gene (ECM1) was performed. Sequencing disclosed a homozygous frameshift mutation, 501insC, in exon 6 (( figure 4 )). The patient was treated with oral acitretin (10 mg on alternate days). However, there was no subjective or objective benefit and therefore treatment was discontinued after 18 months.

Discussion

Our patient presented with clinical features that can be summarized as follows: recurrent cutaneous infections and skin erosions on the head and neck, waxy infiltrated facial skin with atrophic scars, infiltrated ecchymosis-like plaques on the elbows and knees, dysphonia and epilepsy. The association of early hoarseness, waxy infiltration of the skin and a history of an epileptic convulsion suggested the diagnosis of LP, which was confirmed by histologic examination and, in this case by DNA-mutation analysis. Specifically, Hamada et al. have recently shown that lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene ECM1 [9]. In our patient, we identified a homozygous frameshift mutation in exon 6, 501insC. This particular mutation has been found once before in a 30-year-old white male Dutch case of LP [9]. In that patient, the clinical features were slightly more severe, with early onset of laryngeal hoarseness, extensive skin involvement and epilepsy in association with focal intracranial calcification. Nevertheless, our case is considerably younger than the Dutch patient and the difficulty in directly comparing the clinical features of LP patients of different ages with the same ECM1 mutation has been clearly documented [10, 11]. We have also compared the ECM1 haplotype in our patient with the Dutch patient (assessment of intragenic polymorphisms [10] and linkage using the D1S498 microsatellite marker [9]) and both appear to have the same haplotype for the 501insC mutant allele. This suggests a possible common ancestral mutant allele in the white, northern European population, and adds to the database of recurrent and hotspot mutations in lipoid proteinosis [10]. It also has implications for the genetic screening strategy in other individuals of a similar ethnic background.

All pathogenic mutations in lipoid proteinosis appear to result in loss-of-function, with reduced or absent expression of ECM1 [8-12]. However, the precise role of the ECM1 protein in normal human skin is not fully known [13]. ECM1 has two alternatively spliced exons, exon 5a and exon 7, resulting in three ECM1 isoforms. These comprise: ECM1a which contains all exons except for exon 5a, ECM1b which contains all exons except for exons 5a and 7, and ECM1c which contains all 11 exons [13, 14]. ECM1a is expressed in many tissues, including heart, placenta, liver, ovary, kidney, lung, pancreas, testis, muscle, colon, and skin. In contrast, ECM1b has been described only in skin and tonsils. ECM1c is thought to constitute ~15% of total ECM1 mRNA expression in skin [14]. The mutation 501insC in our patient would be expected to result in markedly reduced expression of all three ECM1 isoforms, and therefore the clinical features provide an illustration of the important role of ECM1 in human physiology, especially in the skin. Within the dermis, ECM1 is known to bind to the major heparan sulphate proteoglycan, perlecan [14], and loss of this protein binding in lipoid proteinosis may explain the skin infiltration and scarring, two of the major clinical abnormalities seen in lipoid proteinosis. Delineation of a specific mutation in ECM1 in patients makes DNA-based prenatal diagnosis feasible and could provide a rationale for the development of newer forms of treatment, given the very limited treatment options currently available for individuals with this genodermatosis [15]. Recently the pattern of immunolabelling using a polyclonal anti-ECM1 antibody was reported to be of value in confirming the diagnosis of LP and also to be helpful in determining the appropriate ECM1 mutation detection strategy [16].

Acknowledgements

Mutation studies on the ECM1 gene were supported by grants from the Charitable Foundation of Guy’s and St Thomas’ Hospital and the British Skin Foundation.

References

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