Eyelid Degenerative and Inflammatory Disorders

Approach to diagnosis

• Etiology: thought to be caused by skin rubbing
• Appearance in childhood can be associated with basal cell nevus syndrome.
• Increased incidence with age, no gender/race predilection
• Characteristic appearance: pedunculated, fleshy, skin-colored mass
• Benign, slow growing, usually asymptomatic, sometimes causes irritation
• Most often seen in neck, axilla, and inguinal region
• Definitive diagnosis by histopathology

Risk factors

• Obesity
• Diabetes

Differential diagnosis

• Squamous papilloma
• Verrucca vulgaris
• Amelanotic nevus

Clinical management

• Observation
• Surgical excision
• Cryotherapy

Complications of treatment

Rare; recurrence uncommon

Approach to diagnosis

• Hyperplasia of squamous epithelium
• Characteristic appearance: frond-like, papular lesion, often pedunculated
• Slow growing, usually asymptomatic
• Definitive diagnosis by histopathology
• Fibrovascular core covered by acanthotic epithelium, hyperkeratosis

Risk factors

• Increased incidence with age, no gender/race predilection
• Most common benign eyelid lesion

Differential diagnosis

• Verrucca vulgaris
• Amelanotic nevus
• Seborrheic keratosis
• Basal cell carcinoma

Clinical management

• Observation
• Surgical excision
• Laser ablation (CO₂, argon)

Complications of treatment

Rare; recurrence uncommon

Approach to diagnosis

• Unknown etiology; arises from follicular infundibulum, involves aggregation of immature epidermal keratinocytes
• Increased incidence with age, no gender/race predilection
• Clinical features: elevated, sometimes pedunculated, rough keratotic surface with variable pigmentation, greasy “stuck-on” appearance
  

• Slow growing, usually asymptomatic; sometimes causes irritation
• Commonly seen on torso and face
• Clinical variants:
• Dermatosis papulosa nigra: Multiple deeply pigmented facial SKs in Africans
• Inverted follicular keratosis: Irritated variant of SK, rapid growth typical
• Intraepidermal horn cysts: Thick protuberance of keratin from SK
• Sudden appearance or growth of multiple SKs can herald internal malignancies such as adenocarcinoma of GI or breast (Leser-Trelat sign)
• Definitive diagnosis by histopathology: Hyperkeratosis, papillomatosis, acanthosis

Risk factors

• Family history
• Sun exposure
• Age

Differential diagnosis

• Squamous papilloma (pigmented)
• Nevus
• Melanoma
• Pigmented basal cell carcinoma

Clinical management

• Observation
• Surgical excision
• Cryotherapy

Complications of treatment

Rare; recurrence uncommon

Approach to diagnosis

• Pseudoneoplastic proliferation of epidermis and adnexal epithelium
• Can be idiopathic or associated with numerous types of infection (classically mycotic or mycobacterial), inflammation, trauma, or neoplasms (for example, basal cell carcinoma)
• Epidemiology: increased incidence with age
• History:
• Can develop rapidly over weeks
• Can gradually regress if left untreated for several months
• Clinical features:
• Nodular, irregular, crusty lesion, sometimes ulcerative
• Often resembles cutaneous malignancy
• Variant: keratoacanthoma (see Squamous Cell Carcinoma)
• Diagnosis established by histopathology:
• Irregular invasion of dermis by jagged epidermal masses, horn cysts, mitotic figures, nonspecific inflammation
• Can be difficult to distinguish from squamous cell carcinoma
• Inciting organism can be seen if present

Risk factors

Presence of inciting condition

Differential diagnosis

• Squamous cell carcinoma
• Basal cell carcinoma

Patient management

• Observation (can spontaneously regress)
• Medical therapy
• Treatment of underlying condition if identified
• Surgical excision
• If diagnostic uncertainty exists, consider Mohs excision or frozen section control

Complications of treatment

Scarring, eyelid deformity

Approach to diagnosis

• Etiology unknown
• Epidemiology:
• Increased incidence with age, most common over 40–50
• Rare familial forms exist
• History: gradual onset, chronic course
• Clinical features:
• One or more focal tan-yellow papules or diffuse thickening of eyelids
• Similar to sebaceous adenoma
• Associated with Muir-Torre syndrome (MTS):
• Sebaceous neoplasms or keratoacanthoma
• Internal malignancy (for example, colorectal carcinoma)
• Presence of sebaceous hyperplasia does not necessitate screening for MTS
• Diagnosis established by histopathology: Well-differentiated, mature sebaceous lobules

Risk factors

• Muir-Torre syndrome
• Family history

Patient management

• Observation
• Trichloroacetic acid (small, diffuse lesions)
• Surgical options:
• Excision
• Electrodessication, cautery (small lesions)

Approach to diagnosis

• Etiology: idiopathic, sometimes associated with familial hyperlipidemia
• A large case-control study (n=35,452) found no significant association between xanthelasma and dyslipidemia or cardiovascular disease when rigorously matched ( Lustig-Barzelay, 2025)
• Epidemiology:
• 1–3% incidence in general population, generally between 35 and 55
• Affects women twice as often as men
• History: gradual onset, usually static, but can fluctuate in size/number
• Clinical features:
• Flat or mildly elevated, yellow, subepidermal placoid lesions
  
• Usually bilateral, can involve all 4 lids, medial location common
• Diagnosis usually clinical:
• Atypical appearance should raise suspicion for xanthogranulomatous disease (see below)
• Histopathology: infiltration of superficial reticular dermis foamy histiocytes, Touton giant cells sometimes present
  

Risk factors

Hyperlipidemia

Differential diagnosis

• Xanthoma
• Xanthogranuloma

Patient management (Yee, 2024)

• Observation
• Treatment of hyperlipidemia if present:
• Normalization of lipids can lead to regression
• Trichloroacetic or bichloroacetic acid
• Laser ablation (CO₂, argon, erbium-YAG, pulsed dye), electrosurgery, cryotherapy, plasma and RF-based ablation
• Intralesional injection- bleomycin, pingyangmycin, heparin sodium
• Surgical excision:
• Typically full-thickness, but subepithelial excision if lipid infiltration extends beneath the surface
• Recurrence common regardless of treatment modality:
• Highest incidence of recurrence within first year

Complications of treatment

Cicatricial ectropion/lagophthalmos

Disease-related complications

Cardiovascular risk related to hyperlipidemia

Approach to diagnosis

• Unknown etiology; cell-mediated immune defects
• T_H2-cell activation with increased synthesis of IL-4 and IgE
• Epidemiology:
• Manifests in infancy or childhood
• 2% of population affected by atopic dermatitis
• Characteristic triad:
• Eczematous dermatitis
• Allergic rhinitis
• Asthma
• Clinical features:
• Eyelid findings: eczema, pruritis, edema, violaceous or brown discoloration (“allergic shiner”), lichenification, periocular milia
• Dennie-Morgan fold: skin crease from medial canthus to lower lid
• Secondary staphylococcal infection can occur.
• Ocular findings: atopic keratoconjunctivitis, conjunctival papillae, Horner-Trantas dots, inferior pannus, symblepharon
• Keratoconus: 1.5–6.7% incidence in atopic dermatitis
• Skin hypersensitivity to numerous stimuli/agents
• Establishing the diagnosis
• History and physical exam
• Elevated serum IgE

Differential diagnosis

• Other forms of dermatitis: contact, seborrheic, lichen simplex chronicus
• Blepharochalasis syndrome

Risk factors

Family history of atopy

Patient management

• Natural history
• Infantile stage: eczematous dermatitis affecting extensor surfaces (tops of feet, back of hands, knees, face)
• Childhood phase: flexural sites (popliteal/antecubital fossae)
• Periodic exacerbations and remissions
• Medical therapy
• Break the “itch-scratch” cycle: cool moist compresses, bland ointments, antihistamines
• Acute flares: topical corticosteroids (5–10 days)
• Keratoconjuctivitis: topical antihistamines, mast-cell-stabilizers, corticosteroids, or NSAIDs
• Secondary staphylococcal infection: topical antibiotics
• Topical calcineurin inhibitors Pimecrolimus and Tacrolimus are both indicated for the treatment of atopic dermatitis.
  • Safe and effective for sensitive areas, particularly given the low risk of causing atrophy.
  • Negligible systemic levels after topical application.
  • Boxed warning in US due to theoretical risk of lymphoma and nonmelanoma skin cancers, despite ample evidence suggesting no increased risk with topical use.
• Dupilumab (IL-4/IL-13 receptor antagonist) and topical/systemic JAK inhibitors (e.g., ruxolitinib cream, upadacitinib) have become standard escalation options for moderate-to-severe atopic dermatitis beyond topical calcineurin inhibitors, including periocular disease
• Surgery: not indicated
• Co-management with dermatology recommended

Complications of treatment

• Steroids: skin atrophy, glaucoma, cataract, susceptibility to infection
• Prevention by using short courses of treatment and avoiding long-term use

Approach to diagnosis

• Etiology: exposure to offending agent
• Cosmetics, cleaning products, preservatives, metals, ophthalmic medications, and others
• Can be irritant or allergic (type IV hypersensitivity)
• Epidemiology: female predominance
• Clinical features:
• Acute: edema, erythema, pruritis, vesicles, weeping
• Chronic: erythema, lichenification, hyperpigmentation
• Patch testing with suspected offending agent

Differential diagnosis

• Other forms of dermatitis: atopic, seborrheic, lichen simplex chronicus
• Blepharochalasis syndrome

Patient management

• Remove offending agent
• Medical therapy
• Cool compresses, oral antihistamines
• Topical corticosteroid ointment
  • Low-potency (hydrocortisone 1% cream/ointment, lotemax ointment)
  • Topical dexamethasone ophthalmic suspension for severe/refractory cases
• Topical calcineurin inhibitors (tacorimus, pimecrolimus)
  • Widely used off-label for allergic and irritant contact dermatitis (Approved for atopic dermatitis)
• Topical PDE-4 inhibitor (crisaborole) and topical JAK inhibitor (ruxolitinib 1.5% cream) are now included among alternatives to corticosteroids/calcineurin inhibitors for eyelid dermatitis
• Oral corticosteroids can be considered for acute cases

Complications of treatment and their prevention

• Steroids: skin atrophy, glaucoma, cataract, susceptibility to infection, topical steroid withdrawal (erythematous, edematous, burning plaques on steroid discontinuation)
• Prevention by using short courses of treatment and avoiding long-term use

Approach to diagnosis

• Etiology unknown; associated with increased sebaceous gland number and function
• Yeast (Pityrosporon ovale) thought to play a role
• Epidemiology:
• Infancy (“cradle cap”)
• Puberty through adulthood
• Male predilection
• Affects 2–5% of population
• History: gradual onset, worse during winter
• Clinical features:
• Greasy scaling, patchy erythema involving scalp, central face, lids, brow, ears, presternal skin, axilla, inguinal area
• Blepharitis, madarosis, keratoconjunctivitis
• Histopathology:
• Focal parakeratosis
• Pyknotic neutrophils
• Acanthosis
• Spongiosis
• Nonspecific inflammation of dermis

Risk factors

• Parkinson’s disease
• Epilepsy
• Multiple sclerosis
• AIDS

Differential diagnosis

• Psoriasis
• Impetigo
• Dermatophytosis
• Lichen simplex chronicus
• Discoid lupus

Patient management

• Natural history: chronic course with exacerbations and remissions
• Medical therapy:
• Anti-dandruff shampoos
• Ketoconazole shampoo 2% to face during shower or cream
• Corticosteroid cream
• Lid scrubs, topical antibiotics
• Radiation therapy: UV radiation helpful (condition improves in summer, flares in fall)
• Comanagement with dermatology recommended

Complications of treatment

Steroids:

• Skin atrophy
• Glaucoma
• Cataract
• Susceptibility to infection

Approach to diagnosis

• One phenotype within broader category of autosomal recessive congenital ichthyosis (ARCI)
• Etiology: genetic, usually autosomal recessive
• Identified mutations on chromosomes 14q11 and 2q33-35
• Abnormal keratin formation
• Subtype of ichthyosiform dermatoses which also include:
• Dominant ichthyosis vulgaris
• X-linked ichthyosis
• Epidermolytic hyperkeratosis
• Epidemiology
• Incidence 1:250,000–300,000
• History
• Disease evident at birth
• “Collodion baby”: encasement in transparent, parchment-like membrane that spontaneously sheds within 2 weeks
• Large scales develop after membrane sheds
• Clinical features
• Cicatricial ectropion and lagophthalmos (Figure 1A)
• Generalized fish-like scales over entire body (Figure 1B)

Figure 1. Two-week-old old infant with lamellar ichthyosis. A. Cicatricial lagophthalmos and ectropion of all four lids. B. Generalized scaling as demonstrated on abdomen (Oestreicher 1990).

• Corneal scarring: might not be completely attributable to exposure (Cruz 2000)
• Testing and evaluation for establishing the diagnosis
• Physical findings
• Skin biopsy
• Genetic testing

Risk factors

Family history

Differential diagnosis

Limited

Patient management (Mazereeuw-Hautier, 2025)

• Natural history: chronic and unremitting
• Medical therapy
• Skin moisturizers/emollients and keratolytics
• Less severe in warm, humid climates
• Vitamin D analogues (topical and systemic): emerging support
• Oral retinoids (acitretin) are used for severe ectropion and scaling
• JAK inhibitors may be emerging as targeted therapy
• Gene therapy- pre-clinical development, may result in disease-modifying treatment rather than treating symptoms
• Surgery: anterior lamellar grafts for cicatricial ectropion
• Donor sites for full-thickness skin grafts limited due to generalized involvement
• Penile foreskin (Uthoff 1994)
• Maternal allograft (Das 2010)
• Oral mucous membrane graft (Nayak 2011)
• Human engineered skin (Culican 2002)
• Inverting sutures (with systemic retinoids) for ectropion
• Advancement flaps
• Non-surgical options
  • Hyaluronic acid filler injection for eyelid retractions/ectropion
  • Scleral/PROSE lens, moisture goggles, amniotic membrane

Disease-related complications

Disease-related complications are syndrome-related: Refsum syndrome, Gaucher syndrome.

Approach to diagnosis

• Classifications: antibody-defined phenotype model, dividing into 8 groups: adult DM, juvenile DM, amyopathic DM, cancer-associated DM, polymyositis, immune-mediated necrotizing myopathy, inclusion body myositis, and overlap myositis
• Myositis-specific antibodies now drive both prognosis and treatment selection
• Rather than a single autoantibody panel used mainly for diagnosis, specific antibodies now define distinct clinical phenotypes with different treatment algorithms
• The precise underlying autoimmune trigger remains incompletely understood
• Etiology: tyle I interferon-driven autoimmune vasculopathy
• Genetic susceptibility and environmental trigger model (viral infection)
• Auto-antibody-defined mechanism: specific antibody subtypes have been identified
• Environmental/infectious triggers
• Viral (coxsackievirus, parvovirus, HTLV-1, HIV, COVID-19)
• Drug-induced (for example, atorvastatin, phenytoin)
• Paraneoplastic: ovarian or gastric carcinoma, lymphoma, lung cancer, and others
• Epidemiology
• Can present in children (5–15 years) or middle-aged adults
• Female preponderance
• History: variable presentation, rash usually appears early
• Clinical features
  • Periobital
    • Bilateral heliotrope rash on upper lids or malar region (Figure 2)

Figure 2. Heliotrope rash and edema of both upper eyelids in 16-year-old male with juvenile dermatomyositis (Taban 2006).

• Diffuse purple discoloration or scaly erythema — variant: supraciliary “purple line”
• Periorbital edema
• Pox-like scars (late stage)
• Combination of periorbital heliotrope erythema with eyelid edema (PHEEE) has been proposed as a specific clinical marker for paraneoplastic dermatomyositis, particularly in patients with anti-TIF1-γ or anti-NXP-2 autoantibodies (Aliu, 2024)
• Anterior and posterior segment findings of vasculopathy (episcleritis, iritis, cotton wool spots, vision loss)
• Cutaneous:
  • Calcinosis cutis, a hallmark of chronic disease (mostly in children)
  • Mechanic’s hand: fissured, scaly, hyperkeratotic, hyperpigmented hands
  • Gottron’s papules (pathognomonic): scaly erythematous plaques over knuckles, elbows, and knees
  • “Shawl” pattern rash over shoulders/arms/upper back/anterior neck/chest
• Gastrointestinal: Dysphagia, proximal muscle weakness
• Pulmonary: interstitial lung disease in 1/3 of patients; risk of morbity/mortality if present
• Arthritis, arthralgias- in 50% of patients, involving small joints
• Cardiac conduction defects
• Testing and evaluation for establishing the diagnosis
• 2017 EULAR/ACR Classification Criteria  (EULAR/ACR Classification Criteria paper)calculates a probability score for idiopathic inflammatory myopathy (IIM) that classifies patients into possible/probable/definite categories rather than a binary yes/no
•  If a pathognomonic DM skin rash (heliotrope, Gottron papules/sign) is present, the criteria can classify DM without requiring muscle biopsy; in the absence of a classic rash, biopsy is required for diagnosis
• Labs: creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), liver enzymes, ANA, Myositis-specific and myositis-associated autoantibody (MSA/MAA) panel
• Electromyography – can guide muscle biopsy site selection
• MRI- evidence of active myositis within 6 months- supporting evidence
• Muscle biopsy- required when pathognomonic skin findings absent
• Mixed B- and T-cell perivascular infiltrate
• Perifascicular muscle fiber atrophy
• Skin biopsy- nonspecific findings overlapping with lupus erythematosus
• Systemic evaluation:
• pulmonary (CT chest, pulmonary function tests)
• malignancy screening- based on antibody profile

Risk factors

• Viral infection, possibly Lyme disease
• Cancer: ovarian, gastric, lymphoma, others

Differential diagnosis

• Lichen planus
• Seborrheic dermatitis,
• SLE, psoriasis
• Contact dermatitis
• Atopic dermatitis
• Trichinosis

Patient management

• Medical therapy
  • IVIG (Octagam 10%)
  • JAK inhibitors (tofacitinib or baricitinib)
  • Biologics (rituximab, anifrolumab tocilizumab) – case-level evidence
  • Physical therapy for atrophy and contractures
  • Sun avoidance
• Surgery: limited role
• Other management considerations
• Treat overlap syndromes if present
• Treat underlying malignancies if present
• Long-term treatment required

Complications of treatment

Medication-specific

Disease-related complications

• Pulmonary interstitial fibrosis
• Dysphagia
• Cardiac dysfunction
• Infection

Approach to diagnosis

Two major forms:

• Localized scleroderma (morphea)
• Patterns of involvement: circumscribed, linear, generalized, bullous, deep
• Linear scleroderma can involve frontoparietal region (en coup de sabre)
• Systemic scleroderma (progressive systemic sclerosis)
• Multisystem involvement of skin, lungs, heart, GI tract
• Potentially fatal
• Clinical variant: CREST syndrome
• Calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia
• Etiology unknown
• Autoimmune cutaneous sclerosis
• Possible association with Borrelia burgdorferi
• Epidemiology
• Localized: onset typically within first two decades.
• Systemic: middle age
• Female preponderance
• History: initial inflammatory phase followed by quiescence
• Clinical features
• Localized
• Cutaneous white or brown plaques, sometimes with violaceous border
• Patterns: single, linear, or widespread
• Frontoparietal: unilateral linear plaque or scar extending from brow to forehead — en coup de sabre, “strike of the sword” — can cause hemifacial atrophy and involve orbit, leading to enophthalmos
• Other ocular findings (uncommon): anterior uveitis, episcleritis, strabismus, Brown syndrome
• Systemic
• Diffuse cutaneous sclerosis, acrosclerosis, flexion contractures
• Can cause periorbital edema (early)
• Mask-like facies, small sharp nose, microstomia
• Testing and evaluation for establishing the diagnosis
• Nailfold capillaroscopy – Characteristic "scleroderma pattern" capillary changes (enlarged capillaries, capillary loss, pericapillary hemorrhage)
• Auto-antibody panel – ANA, ssDNA, RF, polyclonal IgG, IgM, hypergammaglobulinemia, anti-centromere, anti-topoisomerase I (anti-Scl-70), and anti-RNA polymerase III, with anti-Th/To and anti-U3 RNP
• Histopathology: vascular changes, deposition of collagen in dermis and subcutis, nonspecific inflammation

Risk factors

Unknown

Differential diagnosis

• Localized:
• Lichen sclerosis et atrophicus
• Progressive hemifacial atrophy (Parry-Rhomberg syndrome)
• Systemic:
• Mixed connective tissue disease
• Systemic lupus erythematosis
• Dermatomyositis
• Graft-versus-host disease

Patient management

• Medical therapy: systemic disease
• Corticosteroids beneficial early
• Mycophenolate mofetil
• Nintedanib (multi-targeted tyrosine kinase inhibitor, antifibrotic)
• Tocilizumab (anti-IL-6 receptor antibody)
• Rituximab
• Surgery: en coup de sabre
• Orbitofacial reconstruction for hemifacial atrophy, micro-fat grafting

Disease-related complications

• Systemic
• Cardiac conduction defects
• Heart failure
• Pulmonary fibrosis
• Renal failure
• Malignant hypertension
• Localized
• Epilepsy
• Arthritis
• Flexion contractures

Approach to diagnosis (StatPearls. "Systemic Lupus Erythematosus." Updated 2026)

• Etiology: a multifactorial autoimmune disease arising from loss of immune tolerance in genetically susceptible individuals, with autoantibody production against nuclear and cytoplasmic antigens driving immune complex deposition and tissue damage.
• Type I interferon-driven autoimmune mechanism, with cytokine dysregulation
• Discoid lupus erythematosus (DLE) is the most common subtype of chronic cutaneous lupus erythematosus (CCLE)
• Epidemiology
• Female predilection (9:1)
• Typically middle-aged (median age 40)
• History
• Typically isolated skin lesions; about 90% have no concomitant systemic/pathologic diagnosis at presentation
• Chronic course, typical time to presentation 2 years
• Clinical features
• Symptoms: localized redness, irritation of photoexposed areas
• Erythematous plaque, scaling, madarosis, central hypopigmentation with peripheral hyperpigmentation
• Telangiectasia, ulceration, edema less common
• Can mimic epithelial malignancy
• Isolated or multifocal, unilateral or bilateral
• Associated lesions on face/ears/scalp: about 30%
• Diagnostic testing
  • Physical exam
  • Auto-antibody serology: Antinuclear antibody (ANA) test: 18% positive
• Histopathology
• Interface dermatitis
• Vacuolar degeneration
• Perifollicular/perieccrine inflammation
• Keratinocyte necrosis (Civatte bodies)
• Follicular plugging
• Intradermal mucin deposition
• Pseudocarcinomatous hyperplasia
• Immunoflourescence: lupus band test

Risk factors

• Smoking
• UV exposure (disease exacerbation)

Differential diagnosis

• Premalignant/malignant lesions: actinic keratosis, squamous cell carcinoma, basal cell carcinoma, sebaceous carcinoma, cutaneous T-cell lymphoma
• Inflammatory: blepharitis, chalazion, eczema, psoriasis, seborrheic dermatitis, contact dermatitis, sarcoidosis
• Infectious: preseptal cellulitis, orbital cellulitis, mycotic dermatitis

Management

• Disease course typically chronic, unremitting, nonprogressive
• Medical treatment (Hannon, 2021)
  • First-line:   
    • Oral antimalarials: Hydroxychloriquine Maximum daily HCQ dose: ≤5.0 mg/kg real body weight (max 400 mg qday); response usually seen within 2–3 months; can reduce to 200 mg qd
      • Addition of mepacrine 100 mg/day if inadequate response
      • Substitute chloroquine 4 mg/kg/day if combination fails
      • Maintain treatment for 1–2 years
    • Corticosteroids: often inadequate as monotherapy, first-line
      • Topical (0.05% fluocinonide), intralesional, or oral
  • Second-line
    • Mycophenolate, methotrexate, and thalidomide/lenalidomide
    • Anifrolumab (anti-IFNAR1 monoclonal antibody, type I interferon receptor blockade)- most extensively studied for refractory disease
    • Emerging: Deucravacitinib (allosteric TYK2 inhibitor, oral), Litifilimab (plasmacytoid dendritic cell-directed therapy, targets BDCA2 receptor), Iberdomide (cereblon-targeting ligand) and belimumab (B-cell-directed therapy)
• Surgical excision: rarely used
• Consider referral to dermatology and/or rheumatology

Complications of treatment

• Medication-specific
• Surgical excision can lead to lid retraction/ectropion

Disease-related complications

• Unrecognized/untreated periorbital DLE can lead to cicatricial complications: trichiasis, ectropion, entropion, retraction, lagophthalmos, symblepharon
• Minority of patients w/ DLE (5%) progress to systemic lupus (SLE)
• Ocular manifestations: keratoconjunctivitis sicca, peripheral ulcerative keratitis, interstitial keratitis, retinal vasculopathy
• Systemic complications: cardiac, renal, pulmonary, hematologic, arthritis, dermatologic (malar “butterfly” rash), neurological, psychiatric

Approach to diagnosis

• Classification:
• Adult onset xanthogranuloma (AOX)
• Adult onset asthma with periocular xanthogranuloma (AAPOX)
• Necrobiotic xanthogranuloma (NXG)
• Erdheim-Chester disease (ECD)
• Etiology
• Genetic mutation: BRAF V600E mutation in Erdheim-Chester disease (McKelvie 2017)
• IgG4-related disease (IgG4-RD) overlap: A substantial proportion of AOXGD cases show increased IgG4-positive plasma cells on histopathology, raising the question of whether AOXGD and IgG4-RD represent overlapping or entirely separate entities
• Epidemiology
• Can presents in early adults to elderly patients
• Male preponderance: AAPOX, ECD
• No gender predilection: AOX, NXG
• Clinical features
• Bilateral, indurated yellow-orange subcutaneous lesions
• “Atypical xanthelasma”
• Can be ulcerated in NXG
  
• Often extend deep into orbit
• Systemic associations:
• AOX: typically isolated
• AAPOX: adult onset asthma
• Lid lesions usually appear months after onset of asthma
• NXG: paraproteinemia, multiple myeloma
• ECD: infiltration and fibrosis of internal organs — heart, lungs, retroperitoneum, bones, etc.
• Testing and evaluation for establishing the diagnosis
• Histopathology: sheets of mononucleated foamy histiocytes infiltrating orbicularis/orbital tissue, lymphocytes, plasma cells, Touton giant cells
• IgG4 immunostaining
• BRAF V600E testing- when ECD suspected

Risk factors

Unknown

Differential diagnosis

• Xanthelasma
• JXG
• Sarcoid
• Amyloid
• Sclerosing orbital inflammation
• Lymphoma, other orbital tumors

Patient management (Maeng, 2020)

• Natural history: chronic unremitting course
• ECD: typically aggressive course, mortality >50%
• Medical therapy
• AOX, NXG: intralesional corticosteroid injection for local disease (Elner 2006)
• Systemic therapy: Rituximab, BRAF inhibitors (vemurafenib) Tocilizumab and sirolimus
• Spontaneous regression has been noted
• Surgical debulking
• Recurrence possible
• Multidisciplinary treatment approach highly recommended

Disease-related complications

The most severe are related to systemic fibrosis (ECD) and paraproteinemia or myeloma (NXG).

Approach to diagnosis

• Classification
• Localized or systemic
• Orbital and conjunctival amyloid usually localized
• Eyelid amyloid usually associated with systemic disease (most common site of skin involvement)
• Primary or secondary
• AL (light-chain deposition) or AA (A-protein)
• Etiology
• Primary: hereditary, idiopathic
• Secondary
• B-cell or plasma cell dyscrasia (e.g., multiple myeloma) — common cause of eyelid amyloid
• Reactive (secondary): rheumatoid arthritis, dermatomyositis, scleroderma, inflammatory bowel disease, tuberculosis
• Epidemiology: typically sixth decade, no gender predilection? May be F>M (Mora-Horna, 2016)
• Clinical features
• Amyloid deposition throughout body (systemic)
• Skin, liver, heart, kidney, tongue (macroglossia), etc.
• Carpal tunnel syndrome
• Orbital presentation
• Multiple bilateral confluent papules, waxy pink or yellow that tend to bleed spontaneously or with slight trauma (“pinch purpura”)
• Slowly enlarging, painless orbital mass
• Recurrent ‘chalazion-like’ or pyogenic granuloma-like lesions
• Testing and evaluation for establishing the diagnosis
• Tissue biopsy: Acellular lightly eosinophilic material
• Staining with Congo red is diagnostic standard
• Apple-green birefringence confirms amyloid under polarized light
• Immunohistochemistry for fibril type
• Mass spectrometric proteomic analysis for subtype distinction when IHC ambiguous
• Systemic workup
• If AL-type (light chain) identified
• Serum and urine protein electrophoresis
• Serum free light chain assay, basic labs (thrombocytosis, proteinuria, increased serum creatinine, increased IgG)
• Bone marrow biopsy
• Referral to hematology/oncology
• Cardiac and renal evaluation
• Imaging: orbital MRI or CT

Risk factors: family history, associated conditions as stated above

Differential diagnosis

• Thrombocytopenic purpura
• Scurvy
• Molluscum contagiosum
• Other lid tumors

Patient management

• Natural history: chronic, unremitting; systemic AL disease often fatal
• Medical therapy
  • Treatment of underlying disorders, if present
  • Chemotherapy – high dose melphalan
  • Steroids
  • Stem cell transplantation
• Radiation therapy (controversial, limited evidence of benefit)
• Surgical debulking (Patrinely 1992)
  • High risk of bleeding due to accumulation of amyloid around blood vessels
  • Recurrence possible
• Multidisciplinary treatment approach recommended for systemic disease

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