|Connective tissue disorders
|Urbach-Wiethe disease; Lipoproteinosis; Hyalinosis cutis et mucosae
|< 500 reported cases
Lipoid proteinosis (LP) is an autosomal recessive condition characterized by progressive deposition of hyaline material in the skin, mouth, upper respiratory tract and other internal organs, first described in 1929. Its main clinical features are thickening of the vocal cords with a hoarse voice, followed by skin thickening and scarring. Mutations in the ECM1 gene have been identified.1
The first clinical symptom of LP is hoarseness together with inability to cry, secondary to thickening of the vocal cords. Skin symptoms usually manifest during the first years of life and initially encompass trauma-induced blistering, hemorrhagic crusting and scarring. Later, they consist of yellowish, waxy, firm papules/plaques that may coalesce to cause diffuse skin thickening due to desposition of hyaline material. Predilection sites are the face, extremities and enoral. A row of beaded papules at the margins of the eyelids, known as moniliform blepharosis, is a characteristic finding and thought to be pathognomonic. Diffuse skin thickening / infiltration worsens over time and is frequently accentuated by warty hyperkeratosis on areas exposed to friction (e.g. knees and elbows). Varicelliform or acneiform scars, sometimes reported to occur spontaneously, as well as pruritus and photosensitivity is present in a subset of patients. Mild alopecia due to scalp infiltration occurs in some patients. Mucosal thickening is evident on buccal mucosa, tongue (with movement restriction), frenulum, pharynx and larynx, occasionally leading to dysphagia and respiratory insufficiency. Involvement of salivary glands may result in xerostomia and poor oral/dental hygiene.
Seizures, psychiatric disorders (e.g. schizophrenia) and memory loss are potential neurological complications. Although extracutaneous involvement is less common, desposits may also be found in the gastrointestinal tract. Ocular involvement (corneal opacities, glaucoma) may occur as well. Generally, the phenotypical expression varies, even within families. LP does not affect lifespan in general, as the disease only slowly progresses and symptoms are usually stable in adulthood.2-6
LP is due to recessive mutation of the ECM1 gene, encoding for the extracellular matrix protein 1, expressed in many organs and important for protein-protein interactions. ECM1 has been shown to play a role in epidermal differentiation, stimulation of angiogenesis and regulating skin vessel homeostasis. It is suggested that inefficient draining of fluids and macromolecules due to the lack of cutaneous lymphatic vessels causes accumulation of protein-rich material in the extracellular matrix. Defective ECM1 protein probably also generates altered protein binding, to basement membrane proteins or associated macromolecules. This could result in accumulation of collagen IV and other non-collagenous proteins that may account for the hyaline material deposition in the skin and other tissues.3, 7, 8
The diagnosis of LP is based on clinical findings and confirmed by histopathologic examination of a lesional skin biopsy. Hyperkeratosis together with PAS-positive, diastase-resistant, thickened basement membrane around dermal vessels and skin appendages as well as focal deposition of hyaline material in the dermis are typical histologic features. The deposited material shows similarities to both lipid and protein. This is why the disease has been labelled “lipoid proteinosis”, although no pathologies in the lipid metabolism are present. Electron microscopy reveals thickening and reduplication of the basement membrane around blood vessels, appendages, smooth muscle cells, nerve endings and beneath the epithelium. Cytoplasmic vacuole formation in dermal fibroblasts and abnormal lysosomes with curved tubular profiles in dermal eccrine glands and histiocytes have also been described. Mutational analysis of the ECM1 gene can confirm the diagnosis.3, 9, 10
Treatment is primarily symptomatic. A multidisciplinary management, involving i.a. dermatology, otolaryngology, neurology, clinical genetics, is recommended. Experimental treatments have shown varying efficacy but only rarely peristent benefits (DMSO, etretinate, D-penicillamine, systemic steroids for oral ulcers). Surgical and carbon dioxide laser procedures for skin lesions may be relevant for some patients as well as microlaryngoscopic surgery. Tracheostomy may be required in case of respiratory insufficiency.11-13
6. Callizo M, Ibáñez-Flores N, Laue J, Cuadrado V, Graell X, Sancho JM. Eyelid lesions in lipoid proteinosis or Urbach-Wiethe disease: case report and review of the literature. Orbit. 2011;30(5):242-244.
8. Smits P, Poumay Y, Karperien M, et al. Differentiation-dependent alternative splicing and expression of the extracellular matrix protein 1 gene in human keratinocytes. Journal of investigative dermatology. 2000;114(4):718-724.
11. Rosenthal G, T LIFSHITZ TM, KACHCO L, ARGOV S. Carbon dioxide laser treatment for lipoid proteinosis (Urbach-Wiethe syndrome) involving the eyelids. The British journal of ophthalmology. 1997;81(3):252.