Background
Lipoid proteinosis (LP) (OMIM 247100), also known as Urbach-Wiethe disease, is a rare autosomal recessive genodermatosis characterized predominantly by hoarseness, variable scarring and infiltration of the skin and mucosa[
1]. LP was first reported by Urbach and Wiethe in 1929, and originally named ‘lipoidosis cutis et mucosae’. This disorder typically presents warty skin infiltration, beaded papules along the eyelid margins, skin scarring, extracutaneous abnormalities, as well as hoarseness of the voice, epilepsy and neuropsychiatric abnormalities[
2]. Histologically, there can be widespread deposition or accumulation of hyaline-like materials and disruption or irregular reduplication of basement membrane around blood vessels and at the dermal-epidermal junction. Since pathological mutations were identified in the extracellular matrix protein 1 gene (
ECM1) in 2002, more than 50 different cases with
ECM1 mutations have been reported thus far, most of which were specific to individual families[
3]. In this paper, we reported a homozygous mutation of
ECM1 gene in a Chinese boy with LP and recurrent anaphylaxis. Notably, we present our experience from a pilot study for treating the patient with therapeutic glucocorticoid.
Conclusion
Lipoid proteinosis is characterized by various degrees of scarring and infiltration of skin and mucosae[
1,
9]. The typical clinical features include hoarseness, beaded eyelid papules, mucosae infiltration of the pharynx, tongue, soft palate, tonsils and lips[
10,
11]. In addition, the fragile skin may be easily damaged by minor trauma or friction, resulting in blisters and scar formation. All of these could be found in our case. Furthermore, histopathological findings of periodic acid–Schiff (PAS)-positive, and deposition or accumulation of hyaline materials in the lamina propria, as well as irregular hyperplasia of epithelium also strongly supported our diagnosis. To date, at least 47 different mutations in the
ECM1 gene have been reported for more than 50 unrelated patients with LP[
3]. Most of them were family specific except for the largest groups of LP patients worldwide in Namaqualand, South Africa, suggesting a founder effect[
12]. Approximately half of all mutations (22 of 47) were located within exon 6 or 7, suggesting a hot spot of mutations for this disorder. In this study, we identified a homozygous mutation also located on the exon 6 (c.658 T > G), which was previously observed in three additional unrelated Chinese families[
4]. Since this mutation has not been detected in patients from any other races, it may represent an ancestral allele in Chinese Han population.
The human
ECM1 gene was isolated in 1997 and mapped to chromosome 1q21[
13]. ECM1 can stimulate blood vessel endothelial cell proliferation and angiogenesis. Within the epidermis, however, ECM1 is able to influence the differentiation of keratinocyte. After secreted into the dermis, ECM1 acts as a “biological glue” by binding to glycosaminoglycans and fibrillar protein growth factors, and then regulates basement membrane and interstitial collagen fibril macro-assembly and growth factor binding. Therefore, a loss-of-function mutation in
ECM1 gene may induce a strange pattern of keratinocyte maturation and differentiation, as well as dysregulation of dermal homeostasis and clinical features of skin infiltration and scarring[
12,
14] (see Additional file
6).
Although many therapeutic trials have been tested to alleviate LP symptoms, including oral steroids, oral dimethyl sulphoxide (DMSO) and intralesional heparin, as well as D-penicillamine and acitretin[
9,
15‐
17], no convincing evidence has been found to support any sustained treatment benefits. In our study, local injection of compound betamethasone and oral application of hydrocortisone have dramatically alleviated the patient’s symptoms such as thickened mucosa and recurrent anaphylaxis, and the treatment was well tolerated. We postulate that one of the possible mechanisms underlying it might be associated with the inhibitory effects of glucocorticoid on the matrix metalloproteinases (MMP-9) functions. Firstly, anaphylaxis with elevated IgE may activate mast cell to secrete tumor necrosis factor alpha (TNF-α) and to induce the proMMP-9 to be an active enzyme[
18]. Secondly, the activated mast cell will further induce the MMP-9 to be released from fibroblasts through both adhesive interactions and the release of TNF-α from mast cells itself[
19,
20]. Thirdly, MMP-9 activation and overproduction are proved to be associated with the occurrence and development of some inflammatory reaction and anaphylaxis[
21,
22]. We thus assume that the application of glucocorticoid, by targeting the MMP-9 molecule, a key mediator in both LP and anaphylaxis, as well as in some inflammations, would alleviate the anaphylactic reaction in skin and mucosa lesions in LP. The postulated mechanism underling the effect of glucocorticoid on LP patients is shown (see Additional file
6). However, further experiments and prospective, randomized, controlled clinical trials are in need to verify this hypothesis and long-term therapeutic effects as well as the safety of glucocorticoid for treatment of LP.
In summary, we identified a hot C220G mutation of the ECM1 gene in a child with LP, suggesting a founder effect for this allele in Chinese patients. More importantly, modified glucocorticoid application can significantly improve the symptoms of the patient suffering from LP and recurrent anaphylaxis with no side effects. Our experience and therapeutic protocol could be applied and verified in appropriate LP patients particularly complicated with recurrent anaphylaxis or associated chronic inflammation.
Acknowledgments
Authors are grateful to patients for their important contribution to this study. Work was supported by the Genetic Disease Research Fund (2011) at School of Stomatology, the Fourth Military Medical University (FMMU), China. No additional external funding was received for this study. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interest
As a disclaimer, Tao Cai represented his own perspective in the paper, not the NIDCR/NIH. All remaining authors declare the absence of any Conflict of Interest.
Authors’ contributions
RZ and YL performed mutation analysis and data interpretation, drafted the manuscript; YX, performed data analysis; YW, performed quality control of pathological data; RZ, YL and XW participated in samples’ collection and data acquisition; SS, performed pathological review and data analysis, participated into the design of the study; TC and QW performed data interpretation, conceived of the study, helped to draft the manuscript. All authors read and approved the final manuscript.