Continuing Education Activity

Lipoid proteinosis is an autosomal recessive condition characterized by hyaline-like deposits in the skin, mucous membranes, and other parts of the body. It is caused by a mutation in the extracellular matrix 1 (ECM1) gene. This activity reviews the evaluation and management of lipoid proteinosis and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Summarize the etiology of lipoid proteinosis.
• Describe the most common physical exam findings in patients with lipoid proteinosis.
• Outline the epidemiology of lipoid proteinosis.
• Review some interprofessional team strategies that the healthcare team can use to improve outcomes in patients with lipoid proteinosis.

Introduction

Urbach and Wiethe first described lipoid Proteinosis (LP) (hyalinosis cutis et mucosae) in 1929.[1] LP is a rare genodermatosis characterized by the deposition of hyaline-like material in various tissues and organs. LP is associated with a variety of characteristic cutaneous and mucosal findings and several neurologic, psychiatric, and gastrointestinal manifestations.[2][3][4][5][6]

Etiology

LP is caused by a homozygous or compound heterozygous loss-of-function mutation in the extracellular matrix protein 1 (ECM1) gene located on chromosome 1q21.[7][8][9] Most ECM1 mutations are frameshift or nonsense mutations in exons 6 or 7, resulting in a truncated ECM1.[8] The ECM1 gene encodes glycoproteins essential for basement membrane and extracellular matrix structure integrity, skin adhesion, and protein-protein interactions.[9][10] Since there are various ECM1 splice variants and mutations, many LP genotypes and phenotypes are possible.[8][10] 

LP is inherited in an autosomal recessive pattern. Patients often have affected family members, and some are children of consanguineous parents.

Epidemiology

LP occurs worldwide but is rare, with only about 400 cases reported in the medical literature.[10][11][12] Males and females are affected equally.[9] The Namaqualand region in South Africa has the largest LP patients sharing a common mutation, suggesting a founder effect.[12] There is a higher incidence of LP in countries where consanguinity is more common.[13][14]

Pathophysiology

ECM1 is a glycoprotein that plays various extracutaneous roles, including regulation of endochondral bone and cartilage formation, endothelial cell proliferation and angiogenesis, and dendritic cell differentiation.[15] High levels of ECM1 expression may be associated with certain malignancies.[16][17]

In the skin, ECM1 interacts with basement membrane-specific heparan sulfate proteoglycan core protein (HSPG), also known as perlecan, and other proteins important for ECM structure and tissue remodeling like matrix metalloproteinase-9, fibulin-3, and laminin 332.[10][18][19] Certain ECM1 splice variants are expressed within basal keratinocytes and suprabasal cells, indicating a possible role in keratinocyte differentiation.[20]  ECM1 expression is reduced in individuals with chronic ultraviolet light exposure, suggesting an additional role in the cutaneous stress response.[21] Ultrastructural analysis of erosive lesions in a child revealed “free-floating” desmosomes as well as connection loss between some desmosomes and the keratin filament network. This points to a possible role for ECM1 in the attachment between keratin filaments and the desmosome.[22]

Mutations within the ECM1 gene lead to compromised protein-protein interactions and disrupted tissue homeostasis.[8][9][10] Hyaline-like accumulation within different tissues explains many classic clinical findings like hoarseness, moniliform blepharosis, and seizures.

Histopathology

Histologically, LP is characterized by hyaline-like periodic acid-Schiff (PAS)-positive, diastase-resistant deposits within the papillary dermis and at the dermal-epidermal junction (DEJ).[23][24] The basement membrane surrounding blood vessels at the DEJ is reduplicated and structurally disrupted.[25][26] Other blood vessel abnormalities include marked dilation and absence of several groups of vessels (including the dermal papillae capillary loop network, the subcutaneous plexus, and the transverse connecting vessels).[24] Additional histopathologic findings include sweat gland hyalinization and hyperkeratosis.

Immunolabeling can be a useful diagnostic tool, especially early in the disease course. Reduced ECM1 protein in conjunction with characteristic clinical findings should heighten suspicion for LP.[27] Congo-red staining can help differentiate LP from amyloidosis, which is often on the differential diagnosis.

History and Physical

In almost all affected individuals, the earliest manifestation is a weak or hoarse cry in early life due to hyaline-like deposits on the vocal cords.[10][28][29] Hoarseness and severe dysphonia (“husky” voice) can develop and persist throughout life.[30] Deposits within the larynx can occasionally obstruct the airway.[31] 

Cutaneous abnormalities also present early in the disease course, usually beginning with vesicles or bullae and hemorrhagic crusts on sites of friction or trauma, most notably the face and around the mouth.[13]These lesions heal with prominent pox-like or acneiform scarring (Figure A).[32] Over time, the skin can appear thick and waxy with a yellowish hue.[29] Moniliform blepharosis, “beaded” papules along the eyelid margin, is a pathognomonic finding identified in about 50% of patients (Figure B).[33] Other cutaneous manifestations include papules, nodules, plaques on the face and lips, and verrucous and hyperkeratotic lesions at sites of trauma or friction.[29] Early clinical clues, namely cutaneous buttocks lesions, may predict a more severe clinical course with neurologic involvement.[34] There have been infrequent reports of patchy or diffuse alopecia at lesional sites.

Other notable features of LP reflect the infiltrating hyaline-like material throughout the mouth and upper aerodigestive tract. Cobblestone appearance of the oral mucosa, yellow lip nodules, lip eversion, and vegetative lesions and fissures at the lateral commissures can be seen in patients with extensive disease.[6][29][31]

As a result of deposits obstructing Stenson’s duct and secondary xerostomia, patients with LP are prone to frequent upper respiratory tract infections, recurrent parotitis, and dental caries. The submandibular gland can become similarly obstructed and inflamed.[10] The tongue is often “woody” to palpation, with absent dorsal papillae, a shortened and thickened frenulum, and restricted protrusion.[6][35]

Neurologic manifestations of LP can be severe, including epilepsy, dystonia, progressive neuropsychiatric disorders (memory loss and other cognitive impairment, behavioral changes, hallucination, schizophreniform illness), and spontaneous central nervous system (CNS) hemorrhage.[3][36] Hyaline-like material can be deposited throughout the CNS with or without consequent symptomatology.[37] A post-mortem neuropathologic analysis showed calcium accumulation with evidence of adjacent gliosis, vessel calcification, and occlusions with perivascular infarctions, and demyelination.[37] 

Bilateral, symmetric comma-shaped calcification of the amygdala is a pathognomonic radiologic finding. Calcification has also been reported in the hippocampus, basal ganglia, parahippocampal gyrus, uncinate gyrus, striatum, pineal gland, and perirhinal and parietal cortices.[37][38][39] Calcifications develop slowly and are therefore seen more frequently in patients greater than age 10 and in those with longer disease duration.[37][40]

One study of 10 patients with LP radiographically identified six with amygdaloid complex calcification and degeneration and three with decreased perfusion to the medial temporal lobe, suspicious for underlying calcification. Though these nine patients did not differ from healthy controls for cognitive tasks (memory, attention, executive function), they differed from recognizing facial expression, emotional processing, and odor-associative learning and recognition.[39] In an analysis of 7 patients with intracranial calcifications, four had epilepsy with onset in childhood or young adulthood.[36]

Focal seizures were the most common subtype, as demonstrated by video electroencephalography. Patients with certain mutations tended to be resistant to anti-epileptic therapy while others attained seizure-control with levetiracetam and clobazam.[36]   

Finally, there have been rare reports of hyaline-like deposits throughout the digestive tract, some of which regressed with time.[4] One patient presented with acute gastrointestinal hemorrhage as a result of deposits within the small bowel.[4][5]

Evaluation

Because of its autosomal recessive inheritance pattern, patients with LP should be asked about family members with similar symptoms and consanguinity. Synthesis of family history, clinical exam, and histopathologic findings often raise suspicion for LP, though definitive diagnosis can only be made upon identifying an ECM1 mutation. 

 An otolaryngologist should evaluate patients to assess airway involvement and identify any degree of obstruction. Similarly, patients with neurologic or neuropsychiatric symptoms merit evaluation and follow-up with a neurologist and psychiatrist. Neuroimaging may become necessary to identify involved brain regions. 

 Other evaluations will depend on disease manifestations but should include frequent dental, dermatologic, and ophthalmic evaluation.

Treatment / Management

There are been no randomized trials to establish a standard of care for LP. Treatment plans should be individualized based on manifestations of disease and desire for improved cosmetic outcomes. 

Systemic retinoids such as acitretin or etretinate may be effective in treating cutaneous and laryngeal lesions by decreasing the amount of hyaline-like deposits within the dermis.[41] Case reports describing long-term acitretin therapy (0.5mg/kg per day) have noted healing of ulcerated and vesicobullous lesions decrease in tongue size with an improved protrusion,[42] diminished hoarseness and softening of hyperkeratotic verrucous papules and nodules.[43] A few patients who saw improved voice quality had limited, if any, cutaneous improvement.[44][45]

There is conflicting evidence about the efficacy of long-term oral dimethyl sulfoxide (DMSO) for the treatment of cutaneous lesions and hoarseness.[46][47] One case report noted clinical improvement with the chelating agent D-penicillamine 600mg/day.[48]

For patients with vocal cord involvement and impaired phonation, microlaryngoscopy and carbon dioxide (CO) laser procedures can be quite successful.[49][50] However, there is a risk of postoperative granulation tissue formation, fibrosis, and the need for follow-up interventions. For this reason, some argue that surgical intervention is only indicated with a compromised airway.  

To minimize the appearance of scars and moniliform blepharosis, cosmetic procedures such as CO laser, dermabrasion, blepharoplasty, and erbium-doped yttrium aluminum garnet ablative laser have been employed.[51][52][53]

Management of neurologic and psychiatric manifestations of LP should be tailored to each individual. Certain anti-epileptic medications can minimize seizure frequency and severity. Anti-psychotic medication can help manage behavioral changes and psychosis.

Differential Diagnosis

Differential diagnoses may differ between patients. Possible differential diagnoses include:

Cutaneous lesions:

• Herpes simplex infection
• Impetigo
• Epidermolysis bullosa
• Erythropoietic protoporphyria
• Lichen myxedematosus
• Systemic amyloidosis
• Nodular localized cutaneous amyloidosis
• Colloid milium
• Hyalinosis
• Xanthomas
• Scleromyxedema
• Leprosy
• Hydroa vacciniforme
• Incontinentia pigmenti

 Hoarseness:

• Laryngitis
• Laryngotracheitis
• Laryngotracheobronchitis
• Vocal cord nodules
• Gastroesophageal reflux disease
• Vocal cord polyps
• Laryngeal hemangiomas
• Laryngeal cysts
• Vocal cord paralysis
• Vocal cord hypertrophy

 Enlarged tongue:

• Systemic amyloidosis
• Hypothyroidism (congenital)
• Myxedema
• Acromegaly

 Mesial temporal lobe calcification:

• Fahr’s disease
• Calcified glioma
• Raine syndrome
• Healed herpes encephalitis
• Dystonia

Prognosis

LP typically runs a benign but progressive course that is compatible with a normal lifespan. Respiratory obstruction and central nervous system involvement, however, can be life-threatening or impart significant morbidity.  

Complications

LP can cause a wide variety of clinical manifestations due to hyaline deposition in the skin, mucosa, and various organs. Of the possible clinical complications, airway obstruction, seizures, spontaneous CNS hemorrhage are the most severe. Hyaline deposition within the small bowel has also been linked to cases of gastrointestinal bleeding.[4][5]

There can also be complications as a result of surgical intervention on the vocal cords or larynx. These include bleeding, infection, and vocal cord scarring leading to a change in voice quality and a possible need for repeat intervention.

Finally, certain patients may be taking systemic medication to manage their disease, such as anti-psychotic, anti-epileptic, and dopamine-modifying agents. These medications can have a variety of drug-specific side effects.

Consultations

A multidisciplinary approach is recommended for patients with LP. Counseling may involve a dermatologist, otolaryngologist, neurologist, psychiatrist, dentist, and geneticist depending on manifestations of the disease. Like other autosomal recessive conditions, carrier testing and reproductive counseling should be offered to patients and their family members.

Enhancing Healthcare Team Outcomes

LP is a rare genetic disease that requires interprofessional collaboration for optimal patient care. Patients with suspected LP should undergo a comprehensive workup with several specialists, including a dermatologist, neurologist, psychiatrist, otolaryngologist, dentist, and geneticist. It is important to assess disease burden and to evaluate for any possibly life-threatening manifestations. Patients’ symptoms and quality of life should be assessed frequently. Additionally, genetic counseling may offer patients a better understanding of their condition and its mode of inheritance.