Lipoid Proteinosis 

Updated: Apr 17, 2017
Author: Dirk M Elston, MD; Chief Editor: William D James, MD 

Overview

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.

Lipoid proteinosis has been linked to mutations in the gene encoding extracellular matrix protein 1 (ECM1).[1, 2, 3] To date, no effective treatment is known.

See the image below.

Adult male with lipoid proteinosis. His leonine fa Adult male with lipoid proteinosis. His leonine facies appearance is a result of diffuse skin infiltration. Courtesy of Kenneth E. Greer, MD.

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, 4] 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.

Epidemiology

Frequency

More than 300 cases have been reported worldwide.[5] Incidence and prevalence figures are not available.

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.

Prognosis

Lipoid proteinosis has a stable or slowly progressive course, and early manifestations are predictive of outcome.[6]

The presence of this disease is compatible with a normal life span unless altered by airway obstruction or fatal seizure activity.

Mortality rates in infants and adults are slightly increased because of laryngeal obstruction. Patients with significant airway compromise may require permanent tracheostomy.

Patient Education

The parents should be educated about the risk of having affected offspring.

 

Presentation

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, as follows:

  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.[7]

  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.[8]

A positive family history may be elicited because the disease is inherited in an autosomal recessive pattern.[9, 10]

Physical Examination

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.[10, 11]

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.

See the images below.

Waxy skin with atrophic, depressed scars on the fo Waxy skin with atrophic, depressed scars on the forehead. Courtesy of Kenneth E. Greer, MD.
Infiltrated, thickened skin with atrophic and hype Infiltrated, thickened skin with atrophic and hyperpigmented scarring in 2 brothers with lipoid proteinosis. Note the tongues, which are firm and woody, ulcerated, and unable to be completely protruded because of infiltration of the frenulum. Courtesy of Kenneth E. Greer, MD.

Scalp

Involvement manifests as patchy or diffuse hair loss.

Oral cavity

All sites within the oral mucosa may be involved. The tongue is the most commonly affected oral site, and tongue involvement is associated with a history of more affected family members. The palate and gingiva are the least involved mucosal sites.[12]  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.

See the images below.

Beaded papules on the upper labial mucosa. Courtes Beaded papules on the upper labial mucosa. Courtesy of Kenneth E. Greer, MD.
Woody induration and depression of the tongue. Cou Woody induration and depression of the tongue. Courtesy of Kenneth E. Greer, MD.

Upper airway

Infiltration of the larynx, vocal cords, and surrounding structures may produce hoarseness, dysphagia, and airway obstruction.[10]

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, 13]

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.

Complications

Laryngeal involvement may lead to airway obstruction. Vocal cord involvement may lead to impaired speech.

Intracranial calcifications may result in seizures, behavioral changes, rage attacks, and dystonia.

The deposition of hyaline in the small bowel is reported to cause gastrointestinal bleeding.

 

DDx

 

Workup

Laboratory Studies

No laboratory findings are consistently abnormal. The erythrocyte sedimentation rate may be elevated and is thought to be a result of increased production of alpha- and beta-globulins.

Polymerase chain amplification and direct nucleotide sequencing of the ECM1 gene can confirm the diagnosis.

Immunolabeling of affected tissue with polyclonal antibodies against the ECM1 protein may provide a faster, more efficient way of detecting mutations in the near future.[14]

Imaging Studies

A pathognomonic finding on plain radiographs and CT scans of the brain is bilateral, intracranial, bean-shaped calcifications within the hippocampal region of the temporal lobes.

Other Tests

Porphyria should be excluded with appropriate blood and urine screening.

Procedures

Skin biopsy of affected cutaneous or mucosal sites confirms the diagnosis in most cases.

Histologic Findings

Early lesions have eosinophilic hyaline thickening of papillary dermal capillaries. Later, hyperkeratosis is present, and the papillary dermis is widened by hyaline material arranged perpendicular to the basement membrane zone. Hyaline deposits may be arranged around the hair follicles, eccrine glands, sebaceous glands, and arrector pili muscles and nerves in an onionskin arrangement. The hyaline material stains positively with periodic acid-Schiff stain and is resistant to diastase. It also stains positively with colloidal iron and Alcian blue at a pH of 2.5 and with Sudan black and oil red O.

 

Treatment

Medical Care

No cure is known. The disease follows a stable, chronic course but may fluctuate in intensity. No uniformly successful treatment is available.

Scattered anecdotal reports have described successful treatments, but they are not widely applicable.

A single case report demonstrated that continuous treatment with the chelating agent D-penicillamine produced both clinical and histological improvement.[15]

Another single case report demonstrated resolution of skin lesions after 3 years of continuous treatment with oral dimethyl sulfoxide (DMSO). However, a more recent report showed no benefit of DMSO in 3 patients at an average treatment duration of 3 years.[16]

Treatment with potent topical corticosteroids has also shown benefit by healing of lesions and prevention of new lesion formation in a single case report.

Acitretin at a dose of 0.5 mg/kg/day for up to 6 months demonstrated improvement in the hoarseness, appearance of vesiculobullous lesions, and palmoplantar hyperkeratosis.[17, 18]

Seizures, if present, may be treated with appropriate anticonvulsant medications.

Surgical Care

Surgical resection of vocal cord papules has been useful in improving vocal quality. Carbon dioxide laser ablation has been used to treat vocal cord lesions.[19]

Dermabrasion may improve the appearance of skin lesions.

Consultations

Lipoid proteinosis is a chronic disease that can involve many organ systems. Consultations with the appropriate specialists, depending on the system involved, are indicated.

Pediatricians should follow patients for routine health issues and for developmental, emotional, and cognitive progress.

A neurologist should assess and manage seizures.

Dermatologists can aid in diagnostic confirmation with assessment of clinical features and appropriate biopsies. Scar revision may be possible with dermabrasion, laser therapy, and other specialized techniques.

Otorhinolaryngologists can assess airway and vocal cord involvement and can plan surgical intervention as indicated.

Geneticists can review the family history and provide reproductive counseling.

 

Medication

Medication Summary

No pharmacotherapeutic agents have been established as effective for the treatment of lipoid proteinosis.