Greither Disease

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Greither Disease: A Comprehensive Medical Review

Introduction

Greither disease, also known as transgrediens et progrediens palmoplantar keratoderma, is a rare inherited genodermatosis first described by Greither in 1952. According to trusted medical organizations including Orphanet and the National Organization for Rare Disorders (NORD), this condition is characterized by diffuse keratoderma of the palms and soles that progressively extends to the dorsal aspects of the hands and feet (transgrediens) and worsens with age (progrediens). The disease is classified among the hereditary palmoplantar keratodermas and represents a distinct clinical entity with specific genetic underpinnings and characteristic clinical manifestations.^[1]^[2]^[3]

Definition and Classification

Disease Definition

According to Orphanet, the European reference portal for rare diseases, Greither disease is defined as “a rare, isolated, diffuse palmoplantar keratoderma disorder characterized by red-yellow, moderate to severe hyperkeratosis of the palms and soles, extending to the dorsal aspects of the hands, feet and/or wrists and involving the skin over the Achilles’ tendon (transgrediens), gradually worsening with age (progrediens)”.^[1]

Synonyms and Terminology

The condition is known by several names in medical literature:^[2]^[1]

Transgrediens et progrediens palmoplantar keratoderma
Keratosis extremitatum hereditaria progrediens
Keratosis palmoplantaris transgrediens et progrediens
Progressive diffuse palmoplantar keratoderma (PPK)
Progressive diffuse PPK

Classification System

Greither disease is classified within the broader category of hereditary palmoplantar keratodermas as:^[4]^[5]

Type: Non-epidermolytic palmoplantar keratoderma
Pattern: Diffuse transgrediens
Inheritance: Autosomal dominant with variable penetrance
Genetic basis: Mutations in the keratin 1 (KRT1) gene

Epidemiology and Demographics

Prevalence and Incidence

Greither disease is an extremely rare condition with limited epidemiological data available:

Global Prevalence: According to Orphanet, the prevalence is estimated at less than 1 per 1,000,000 individuals worldwide.^[1]

Geographic Distribution: Cases have been reported globally, with particular documentation in European populations, though the true geographic distribution remains unclear due to the rarity of the condition.^[6]^[3]

Family Studies: The largest reported family study documented 10 affected members across 6 consecutive generations, demonstrating the autosomal dominant inheritance pattern with variable penetrance.^[3]

Demographic Characteristics

Age at Onset: The condition typically manifests during childhood, usually after 2 years of age. Most cases present between ages 2-16 years, though late-onset cases have been reported.^[7]^[8]^[9]^[6]

Gender Distribution: The condition affects both males and females equally, consistent with its autosomal dominant inheritance pattern.^[8]^[6]^[7]

Consanguinity: Unlike autosomal recessive palmoplantar keratodermas, consanguinity is not typically associated with Greither disease due to its dominant inheritance pattern.^[6]^[8]

Pathophysiology and Molecular Mechanisms

Genetic Basis

Keratin 1 (KRT1) Gene Mutations: Research has identified mutations in the KRT1 gene as the underlying cause of at least some cases of Greither disease:^[10]^[4]

Specific Mutations: A dominant missense mutation resulting in the amino acid change N188S in K1 has been identified in affected families.^[10]

Molecular Mechanism: Keratin 1 is a type 2 keratin that dimerizes with type 1 keratins 9 and 10 in the epidermis of palmoplantar skin. Mutations in KRT1 disrupt the normal structure and function of intermediate filaments, leading to the characteristic hyperkeratotic changes.^[4]

Phenotypic Variability: The presence of different underlying gene defects may explain the phenotypic variability observed in reported cases of Greither disease.^[10]^[4]

Cellular Mechanisms

Keratinocyte Dysfunction: Mutations in keratin genes lead to:^[4]

Disruption of intermediate filament structure
Impaired mechanical stress resistance
Abnormal keratinization processes
Excessive keratinocyte proliferation and retention

Inflammatory Component: Histopathological studies reveal chronic inflammatory infiltrates, suggesting an inflammatory component to the disease process.^[7]^[6]

Clinical Manifestations

Primary Clinical Features

The hallmark clinical manifestations of Greither disease include:^[2]^[8]^[6]

Diffuse Palmoplantar Keratoderma:

Moderate to severe hyperkeratosis affecting palms and soles
Red-yellow coloration of affected areas
Well-defined erythematous border around keratotic areas
Progressive thickening with age

Transgrediens Pattern:

Extension to dorsal aspects of hands and feet
Involvement of areas typically spared in other PPKs
Characteristic involvement of skin over Achilles tendon
Extension to wrists and ankles in some cases

Associated Features:

Palmoplantar hyperhidrosis (excessive sweating)^[8]^[2]
Deep fissures and cracks in keratotic areas ^[8]
Maceration of skin, particularly in weight-bearing areas ^[8]

Secondary Manifestations

Extensor Surface Involvement:^[6]^[7]^[2]

Hyperkeratotic plaques on knees and elbows
Psoriasiform lesions on shins
Lichenoid patches on extensor surfaces
Well-defined hyperkeratotic plaques on knuckles

Functional Impairment:

Flexion contractures of fingers and toes
Reduced manual dexterity
Difficulty with ambulation in severe cases
Significant impact on quality of life

Age-Related Progression

Early Childhood (2-5 years):^[6]^[8]

Initial appearance as small raised lesions on fingertips and toes
Gradual progression to involve central palms and soles
Development of erythematous borders

School Age (6-12 years):^[7]

Full development of diffuse palmoplantar involvement
Extension to dorsal surfaces becomes apparent
Hyperhidrosis becomes more prominent

Adolescence and Adulthood:^[2]

Maximum severity typically reached
Potential for some improvement in the fifth decade of life
Functional limitations become more apparent

Diagnostic Approach

Clinical Diagnosis

The diagnosis of Greither disease is primarily clinical, based on characteristic features:^[2]^[6]

Pathognomonic Signs:

Diffuse palmoplantar keratoderma with erythematous border
Extension to dorsal surfaces (transgrediens pattern)
Involvement of Achilles tendon area
Associated hyperhidrosis

Family History: Autosomal dominant inheritance pattern with affected family members across multiple generations.^[3]

Laboratory Investigations

Routine Laboratory Tests: Generally normal in Greither disease:^[7]^[6]^[8]

Complete blood count
Liver function tests
Kidney function tests
Lipid profile (important before retinoid therapy)

Histopathological Examination

Standard Histology:^[3]^[6]^[7]

Orthokeratosis and hyperkeratosis
Acanthosis with prominent keratohyaline granules
Hypergranulosis
Mild mononuclear infiltrate in dermis
Non-epidermolytic changes (absence of cytolysis)

Unique Histological Features: Some cases demonstrate distinctive findings:^[3]

Round, focal areas of orthohyperkeratosis
Located on depressed areas of the epidermis
More prominent hypergranulosis at the bottom of epidermal depressions

Genetic Testing

Molecular Diagnosis:^[10]^[4]

DNA sequencing of KRT1 gene
Identification of specific mutations (e.g., N188S)
Useful for confirming diagnosis and genetic counseling

Limitations: Not all cases of clinically diagnosed Greither disease show KRT1 mutations, suggesting genetic heterogeneity.^[4]

Differential Diagnosis

Primary Differential Diagnoses

Mal de Meleda Syndrome

Distinguishing Features:^[11]^[12]^[13]

Inheritance: Autosomal recessive vs. autosomal dominant in Greither disease
Onset: Present from birth vs. childhood onset in Greither disease
Nail changes: Prominent nail dystrophy in Mal de Meleda vs. normal nails in Greither disease
Palmoplantar involvement: May spare palms and soles in Greither disease vs. always involved in Mal de Meleda
Prognosis: No tendency for spontaneous improvement in Mal de Meleda vs. potential improvement in fifth decade in Greither disease

Vohwinkel Syndrome

Key Differences:

Starfish-shaped keratoses on joints (absent in Greither disease)
Honeycomb palmoplantar keratosis pattern
Associated hearing impairment
Constricting bands around digits (more common in Vohwinkel)

Unna-Thost Palmoplantar Keratoderma

Clinical Distinctions:

Limited to palms and soles without transgrediens pattern
No characteristic involvement of Achilles tendon
Less prominent hyperhidrosis
Different genetic basis (KRT9 mutations)

Secondary Considerations

Epidermolytic Palmoplantar Keratoderma:

Presence of epidermolysis on histology
Different genetic mutations (KRT9)

Papillon-Lefèvre Syndrome:

Associated with aggressive periodontitis
Early loss of teeth
Different genetic basis (CTSC mutations)

Treatment and Management

Current Treatment Approaches

The management of Greither disease is challenging and primarily symptomatic, as there is no curative treatment available:^[14]^[9]^[7]

Topical Therapies

Keratolytic Agents:^[14]^[7]

Salicylic acid (2-10%): Helps reduce hyperkeratosis
Urea-containing emollients (10-40%): Softens keratotic areas
Lactic acid preparations: Promotes desquamation
Propylene glycol: Enhances penetration of other agents

Topical Corticosteroids:^[7]

Used in combination with keratolytics
Help reduce inflammation and erythema
Limited long-term efficacy

Systemic Therapies

Oral Retinoids (Acitretin):^[7]

Dosing: 25 mg three times per week initially, adjusted based on response
Mechanism: Normalizes keratinization and reduces hyperkeratosis
Efficacy: Moderate to marked improvement reported in case studies
Monitoring: Regular assessment of liver function and lipid levels required

Treatment Response:

Moderate improvement after 2 months of therapy
Marked improvement after 3 months
Resolution of hyperkeratotic plaques on extensor surfaces
Maintenance therapy required to prevent relapse

Supportive Measures

Physical Care:^[9]^[14]

Salt water soaks: Help soften keratotic areas
Mechanical debridement: Careful paring of thickened skin
Proper footwear: Well-fitted shoes to prevent pressure points
Regular moisturizing: Prevents excessive dryness and cracking

Infection Prevention:

Antimicrobial soaps for areas prone to maceration
Topical antifungals for secondary fungal infections
Prompt treatment of bacterial superinfections

Emerging Therapies

Novel Topical Agents: Research into new keratolytic formulations and delivery systems.

Gene Therapy: Theoretical potential for future treatment targeting specific genetic defects.

Targeted Biologics: Investigation of therapies targeting specific inflammatory pathways.

Prognosis and Natural History

Disease Course

Progressive Nature: Greither disease typically follows a progressive course:^[1]^[2]

Childhood: Gradual onset and progression
Adolescence: Maximum severity usually reached
Adulthood: Potential for some improvement in the fifth decade

Functional Impact:^[12]

Significant impact on quality of life
Limitations in manual dexterity and ambulation
Psychosocial effects due to appearance
Occupational limitations in severe cases

Long-term Outcomes

Prognosis:^[9]^[2]

Generally benign: No life-threatening complications
Chronic condition: Requires lifelong management
Variable severity: Some patients experience milder forms
Potential improvement: Some cases show spontaneous improvement with aging

Quality of Life Considerations:^[12]

Significant morbidity from symptoms
Impact on daily activities
Social and psychological effects
Need for ongoing support and management

Complications

Primary Complications:

Secondary bacterial infections
Painful fissures and cracks
Functional impairment of hands and feet
Malodorous hyperhidrosis

Rare Complications:

Digital constricting bands (occasional)
Spontaneous amputation (very rare)
Joint contractures in severe cases

Special Populations and Considerations

Pediatric Considerations

Early Management:^[8]

Age-appropriate treatment approaches
Education of parents and caregivers
School accommodation planning
Psychological support for children

Developmental Impact:

Potential effects on fine motor development
Social integration challenges
Need for modified physical activities

Pregnancy and Reproductive Counseling

Genetic Counseling:

50% risk of transmission to offspring (autosomal dominant)
Prenatal genetic testing available for identified mutations
Family planning considerations

Pregnancy Management:

Safety of topical treatments during pregnancy
Contraindication of systemic retinoids
Monitoring for disease exacerbation

Psychosocial Support

Psychological Impact:

Body image concerns
Social stigma related to appearance
Impact on self-esteem and confidence

Support Services:

Patient support groups
Counseling services
Educational resources for patients and families

Research and Future Directions

Current Research Areas

Genetic Studies:

Identification of additional causative genes
Genotype-phenotype correlation studies
Investigation of modifier genes

Pathophysiology Research:

Understanding of keratin biology
Inflammatory mechanisms
Cellular signaling pathways

Therapeutic Development

Novel Treatment Approaches:

Advanced topical delivery systems
Targeted anti-inflammatory agents
Gene therapy approaches

Clinical Trials:

Evaluation of new retinoid formulations
Assessment of combination therapies
Long-term efficacy and safety studies

Diagnostic Innovations

Improved Diagnostic Methods:

Advanced genetic testing panels
Biomarker development
Non-invasive diagnostic techniques

Classification Refinement:

Better understanding of genetic heterogeneity
Refined classification systems
Personalized treatment approaches

Prevention and Screening

Primary Prevention

Genetic Counseling: Essential for affected families to understand inheritance patterns and reproductive risks.^[10]

Prenatal Diagnosis: Available for families with identified genetic mutations.

Secondary Prevention

Early Recognition: Training healthcare providers to recognize characteristic features for prompt diagnosis and treatment.

Complication Prevention:

Regular skin care to prevent infections
Proper footwear to prevent trauma
Early treatment of secondary complications

Healthcare Management and Multidisciplinary Care

Healthcare Team Approach

Dermatology: Primary specialty for diagnosis and treatment planning.

Genetics: For genetic counseling and testing coordination.

Podiatry: For specialized foot care and orthotic recommendations.

Orthopedics: For management of contractures and functional impairments.

Psychology: For psychosocial support and counseling services.

Long-term Monitoring

Regular Follow-up:

Assessment of disease progression
Monitoring treatment response
Screening for complications
Adjustment of therapy as needed

Quality Measures:

Functional assessment scales
Quality of life measurements
Patient-reported outcomes

Economic Considerations

Healthcare Costs

Direct Costs:

Ongoing dermatological care
Prescription medications (especially retinoids)
Specialized footwear and orthotics
Treatment of complications

Indirect Costs:

Lost productivity due to functional limitations
Caregiver burden
Educational accommodations

Cost-Effectiveness

Treatment Evaluation:

Comparison of different therapeutic approaches
Assessment of long-term outcomes vs. costs
Development of treatment algorithms

Global Health Perspectives

Access to Care

Resource-Limited Settings:

Limited availability of genetic testing
Access to specialized dermatological care
Availability of retinoid medications

Health System Challenges:

Rare disease recognition and diagnosis
Healthcare provider training
Treatment accessibility and affordability

Conclusion

Greither disease represents a rare but clinically significant form of hereditary palmoplantar keratoderma that presents unique diagnostic and therapeutic challenges. As a distinct clinical entity first described in 1952, it exemplifies the complex interplay between genetic mutations, cellular dysfunction, and clinical phenotype that characterizes many genodermatoses.

The identification of KRT1 gene mutations as an underlying cause in some cases of Greither disease has provided valuable insights into the pathophysiology of the condition and has opened avenues for targeted therapeutic approaches. However, the apparent genetic heterogeneity suggests that additional genes and mechanisms remain to be discovered, highlighting the need for continued research in this area.

The clinical presentation of diffuse palmoplantar keratoderma with the characteristic transgrediens pattern, involving dorsal surfaces and the Achilles tendon area, distinguishes Greither disease from other forms of inherited palmoplantar keratodermas. The association with hyperhidrosis and the progressive nature of the condition significantly impact patients’ quality of life and functional capacity.

Current treatment approaches remain largely symptomatic, with oral retinoids showing the most promise for significant clinical improvement. The case reports demonstrating marked improvement with acitretin therapy provide hope for patients and families affected by this condition. However, the need for long-term therapy and potential side effects require careful monitoring and individualized treatment planning.

The differential diagnosis of Greither disease from other hereditary palmoplantar keratodermas, particularly Mal de Meleda syndrome, remains challenging and requires careful attention to inheritance patterns, clinical features, and associated findings. The development of reliable genetic testing for causative mutations will likely improve diagnostic accuracy and enable more precise genetic counseling.

The autosomal dominant inheritance pattern with variable penetrance has important implications for genetic counseling and family planning decisions. The 50% risk of transmission to offspring emphasizes the importance of comprehensive genetic counseling services for affected families.

Future research directions should focus on identifying additional causative genes, developing more effective treatments, and improving our understanding of the relationship between genotype and phenotype. The potential for gene therapy and other targeted therapeutic approaches offers hope for more effective treatments in the future.

Healthcare providers caring for patients with suspected or confirmed Greither disease should be aware of the chronic nature of the condition and the need for multidisciplinary care approaches. Early recognition and appropriate treatment can significantly improve quality of life and functional outcomes for affected individuals.

The rarity of Greither disease underscores the importance of case reporting and collaborative research efforts to advance understanding of this condition. International collaboration and the development of patient registries will be essential for gathering sufficient data to support clinical trials and therapeutic development.

As our understanding of keratin biology and genetic mechanisms continues to evolve, there is reason for optimism that more effective treatments will become available for patients with Greither disease. Until then, symptomatic management with careful attention to quality of life and functional outcomes remains the cornerstone of care for this challenging condition.

The story of Greither disease also highlights the broader challenges faced in rare disease research and treatment, including the need for increased awareness among healthcare providers, improved access to genetic testing and specialized care, and continued investment in research for rare conditions that, while affecting few individuals, can have profound impacts on patients and families.

Greither Disease

Greither Disease: A Comprehensive Medical Review

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