eMedicine Specialties > Dermatology > Metabolic Diseases

Lipoid Proteinosis

Author: Kelly M Cordoro, MD, Fellow and Clinical Instructor, Department of Pediatric Dermatology, University of California at San Francisco; Assistant Professor (On Educational Leave), Assistant Program Director for Resident Medical Education, Department of Dermatology, University of Virginia School of Medicine
Coauthor(s): Michael F Osleber, University of Virginia School of Medicine; Vincent A De Leo, MD, Clinical Professor of Dermatology, Department of Dermatology, College of Physicians and Surgeons of Columbia University; Chairman, Department of Dermatology, Director of Dermatology Residency Training Program, St Luke's-Roosevelt Hospital Center; Chairman, Department of Dermatology, Beth Israel Medical Center
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Updated: Nov 12, 2008

Introduction

Background

Lipoid proteinosis is a rare autosomal recessive genodermatosis characterized by the deposition of an amorphous hyaline material in the skin, mucosa, and viscera. The classic manifestation is onset in infancy with a hoarse cry due to laryngeal infiltration. Skin and mucous membrane changes become apparent clinically, and the disease typically follows a slowly progressive, yet often benign, course. Virtually any organ may be involved, but visceral involvement rarely leads to clinically significant consequences. The exceptions are involvement of the central nervous system and respiratory tract, which may result in seizures and airway obstruction, respectively. Lifespan is otherwise normal.

Recently, lipoid proteinosis has been linked to mutations in the gene encoding extracellular matrix protein 1 (ECM1).^1,2 To date, no effective treatment is known.

Pathophysiology

Lipoid proteinosis is a rare genodermatosis inherited in an autosomal recessive pattern. Clinical features are myriad, and the literature describes considerable variation in severity between affected patients. Heterozygous carriers have an apparently normal phenotype but may have subtle changes such as abnormal dentition.

In 2002, loss of function mutations in the gene encoding extracellular matrix protein 1 (ECM1) on band 1q21 were identified as the cause of lipoid proteinosis.¹ Frameshift and nonsense mutations have been described throughout the gene, although exons 6 and 7 seem to be the most common locations. Mutations at these particular sites appear to have genotype-phenotype relevance. Patients with exon 7 mutations display slightly milder clinical features, while mutations in exon 6 result in a more severe phenotype.

The ECM1 gene product is a glycoprotein with functional roles in skin physiology and homeostasis. ECM1 is involved in keratinocyte differentiation in the epidermis and in regulation of basement membrane integrity, interstitial collagen fibril macroassembly, and growth factor binding in the dermis. The disease is characterized by deposits of hyalinelike material in skin, mucosa, and viscera and is also referred to as hyalinosis cutis et mucosae. The original designation, lipoid proteinosis, refers to the histologic features of the deposited material, which shows similarities to both lipid and protein, although no abnormalities in lipid metabolism have been identified.

ECM1 proteins are also expressed in a number of other tissues, including the placenta, heart, liver, small intestine, lungs, ovary, testes, prostate, pancreas, kidneys, skeletal muscle, and endothelial cells. Its role in wound healing, scarring, and aging is speculated but not yet defined.

The loss of normal function of ECM1 in lipoid proteinosis is associated with a wide range of clinical abnormalities due to infiltration of the skin and viscera with hyalinelike material. The histological correlate is diffuse dermal deposition of hyaline material, basement membrane thickening at the dermoepidermal junction and around adnexa and vessels, and epidermal hyperkeratosis. These findings suggest the strong influence of ECM1 on both epidermal and dermal physiology.

The eosinophilic hyaline material is deposited in all affected organs, although whether this is a primary or secondary phenomenon is unclear. The details of the genotype-phenotype correlation regarding the nature of the hyaline deposits are currently under investigation.

Frequency

International

More than 300 cases have been reported worldwide. Incidence and prevalence figures are not available.

Mortality/Morbidity

Life span is usually normal unless altered by laryngeal obstruction or epilepsy. Patients with significant airway compromise may require permanent tracheostomy.

Race

Patients of European ancestry are most commonly affected, including South African descendants of German or Dutch immigrants. Large kindreds from South Africa have been traced back to a single German male who settled in South Africa in the 17th century.

Sex

No sex predilection is reported.

Age

Patients typically present in early childhood, but manifestations may be present at birth. Some cases may occur in adults. Adults may have subtle skin findings and may present with complications due to visceral deposition.

Clinical

History

• A weak or hoarse cry from birth or starting in early infancy is typical and remains throughout life. Cutaneous manifestations usually arise during the first 2 years of life.
• Skin findings manifest in sequential but overlapping stages.
  1. Initially, an inflammatory, vesicular, and crusted eruption appears on the face and extremities and may resemble impetigo or acne. The lesions are self-limited, occur predominantly in sites of trauma, and ultimately heal with scarring.
  2. The second stage is characterized by dermal deposits of amorphous hyaline material, creating a diffuse, waxy, thickened appearance that is most apparent on the skin of the face, eyelids, axillae, and scrotum, although any cutaneous site is vulnerable.
  3. Verrucous papules and plaques then arise on surfaces subject to friction, such as the elbows, knees, and hands.
• Children may have seizures, behavioral changes, learning difficulties, and rage attacks resulting from characteristic temporal lobe calcifications. A case of striatal calcifications associated with generalized dystonia has been reported.
• A positive family history may be elicited because the disease is inherited in an autosomal recessive pattern.

Physical

Characteristic physical findings are thought to result from the deposition of hyaline material in the skin and mucous membranes.

• Skin
  • Early findings include recurrent, variably sized vesicles, pustules, bullae, and hemorrhagic crusts that arise on the skin and in the mouth and throat. The face and distal extremities are the most common sites. Resolution of the lesions occurs with permanent, poxlike atrophic scarring.
  • Late findings are noted as the child ages; the skin develops a waxy, thickened, yellowish appearance due to dermal infiltration. Papules, plaques, and nodules arise on the face, axillae, and scrotum. A pathognomonic sign is a row of beaded papules along the eyelid margins, resembling a string of pearls; this is termed moniliform blepharosis.
  • Hyperkeratotic, verrucous plaques may arise in sites of trauma, particularly the elbows, knees, and dorsum of the hands. A generalized hyperkeratosis and widespread scale may occur.
• Scalp: Involvement manifests as patchy or diffuse hair loss.
• Oral cavity: All sites within the oral mucosa may be involved. Pebbling of the lip mucosa imparts a cobblestone appearance, which may also involve the tongue and gingiva. Infiltration of the tongue and frenulum results in a woody firmness and impaired mobility. Patients may not be able to fully protrude the tongue, and this may be associated with impaired speech and gustation. Transient swelling and ulceration of the lips and tongue may occur. Hypoplasia or aplasia of the teeth, particularly the lateral incisors and premolars, may occur. Recurrent parotitis may occur as a consequence of infiltration of the Stensen duct.
• Upper airway: Infiltration of the larynx, vocal cords, and surrounding structures may produce hoarseness, dysphagia, and airway obstruction.
• Central nervous system: A classic and pathognomonic radiographic finding is bilateral, intracranial, bean-shaped suprasellar calcifications in the temporal lobe.

Causes

Loss of function mutations in the gene encoding extracellular matrix protein 1 (ECM1) on band 1q21 has been identified as the cause of lipoid proteinosis.^1,2 The exact mechanistic correlation between the genetic mutations described and the clinical manifestations of the disease remains unclear.

The Medscape Genomic Medicine Resource Center may be of interest.

• Search for CME/CE on This Topic »

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