The Genetic Story of Tylosis and Its Connection to Esophageal Cancer
Imagine a family where the appearance of thickened skin on the palms and soles in childhood carries a terrifying implication—an extremely high risk of developing esophageal cancer later in life.
This isn't fiction but the reality for families affected by Howell-Evans syndrome, more formally known as Tylosis with Oesophageal Cancer (TOC). For decades, this rare genetic disorder puzzled scientists who sought to understand the mysterious connection between skin and cancer.
The puzzle deepened when researchers identified an African family with this condition but with a previously unknown genetic variant. This discovery opened new avenues for understanding not just this rare syndrome, but the broader mechanisms of cancer development. The investigation into this family represents a compelling story of scientific detective work that bridges genetics, dermatology, and oncology, offering insights that might eventually help countless others affected by esophageal squamous cell carcinoma worldwide 7 .
TOC follows an autosomal dominant inheritance pattern
95% of individuals with tylosis develop esophageal cancer by age 65
Novel RHBDF2 variant identified in an African family
Tylosis (hyperkeratosis palmaris et plantaris) is a rare genetic disorder characterized by focal thickening of the skin on the palms of the hands and soles of the feet. This specific form is classified as a focal, non-epidermolytic palmoplantar keratoderma (PPK), meaning the thickening occurs in specific areas rather than covering the entire palm or foot, and doesn't involve the skin blistering characteristic of epidermolytic conditions 5 .
Cutaneous symptoms typically appear
Complete penetrance of skin symptoms
95% develop esophageal cancer
For years, scientists knew TOC was inherited in an autosomal dominant pattern—meaning a child need only inherit one copy of the mutated gene from either parent to develop the condition. But the specific genetic culprit remained elusive until relatively recently.
This gene encodes an inactive rhomboid protein called iRhom2 that plays a crucial role in epidermal growth factor receptor (EGFR) signaling, a pathway critically involved in cell growth and proliferation 5 .
The discovery of an African family with a novel RHBDF2 variant added another piece to this genetic puzzle, demonstrating that different mutations in the same gene could cause identical clinical presentations while potentially offering new insights into the structure-function relationships of this protein 7 .
The groundbreaking research that first connected RHBDF2 mutations to TOC employed sophisticated genetic sequencing techniques in a multi-step process:
Researchers began by studying large families with TOC, including ones from the UK, US, and Germany, tracking how the condition was inherited across generations 1 .
Scientists designed a custom capture microarray to isolate specific genomic regions of interest. DNA from an affected individual was fragmented, and relevant sections were captured using this customized approach 1 .
The captured DNA fragments underwent high-throughput sequencing on an Illumina GAIIx platform, generating massive amounts of genetic data for analysis 1 .
Raw sequence data was aligned to the human reference genome, and researchers filtered through genetic variations, focusing on novel mutations not present in public databases of normal human genetic variation 1 .
The experimental results revealed crucial connections between RHBDF2 mutations and esophageal cancer development:
In normal skin, RHBDF2 appeared throughout the epidermis with strong localization to cell membranes. In contrast, tylotic skin showed a reduction of RHBDF2 at the cell membrane, suggesting the mutations disrupt the protein's normal cellular positioning 1 .
Immortalized tylotic keratinocytes demonstrated decreased levels of total epidermal growth factor receptor (EGFR) and displayed a surprising increased proliferative and migratory potential compared to normal cells 1 .
The identified mutations affected amino acids that are highly conserved within the iRhom family, indicating their functional importance across evolution 1 .
These findings collectively suggested that RHBDF2 mutations disrupt normal EGFR signaling, creating a condition of dysregulated cell growth that predisposes to cancer development in the esophagus and altered differentiation in the skin.
| Mutation | Amino Acid Change | Families Identified | Conservation |
|---|---|---|---|
| c.557T→C | p.Ile186Thr | UK, US (independent origins) | Highly conserved |
| c.566C→T | p.Pro189Leu | German | Highly conserved |
| c.562G→A | p.Asp188Asn | Additional cases | Highly conserved |
| Novel African variant | Not specified | African family | Not specified |
Understanding and diagnosing TOC requires specialized research reagents and clinical tools that enable scientists and doctors to unravel this complex condition at both molecular and clinical levels.
| Research Tool | Specific Example | Application in TOC Research |
|---|---|---|
| Custom Capture Microarray | Roche NimbleGen custom array | Isolating specific genomic regions for sequencing |
| Sequencing Platform | Illumina GAIIx | High-throughput DNA sequencing |
| Antibodies for Detection | Rabbit-anti-RHBDF2 (Sigma, HPA018080) | Detecting RHBDF2 protein localization in tissues |
| Cell Culture Models | Immortalized tylotic keratinocytes | Studying cell behavior and EGFR signaling |
| Pyrosequencing Assay | PSQ 96MA System (Biotage) | Validating mutations and screening family members |
| Confocal Microscopy | Zeiss Meta-510 LSM | Visualizing protein distribution in skin sections |
The clinical management of TOC requires regular surveillance and specialized care approaches:
| Surveillance Method | Frequency | Purpose and Findings |
|---|---|---|
| Annual Gastroscopy | Yearly | Early detection of esophageal dysplasia or cancer |
| Esophageal Biopsies | During each gastroscopy | Quadratic biopsies from upper, middle, and lower esophagus |
| Physical Examination | Regular intervals | Monitoring palmoplantar keratoderma and complications |
| Genetic Counseling | At diagnosis and as needed | Informing patients and families about inheritance and risks |
| Symptom Management | As required | Addressing skin discomfort, fissures, and infections |
The discovery of novel RHBDF2 variants in diverse populations, including the African family, highlights the global distribution of this condition and emphasizes the importance of including diverse populations in genetic research. This inclusion helps ensure that diagnostic tests and potential treatments benefit all populations, not just those of European descent where the condition was first described.
Research on TOC has revealed crucial insights into EGFR signaling pathways that extend far beyond this rare syndrome. Since EGFR signaling is disrupted in many common cancers, understanding how RHBDF2 mutations dysregulate this pathway may lead to novel therapeutic approaches for multiple cancer types 1 9 .
Interestingly, recent research has uncovered connections between RHBDF2 and other cancers, including kidney renal clear cell carcinoma (KIRC), where high levels of RHBDF2 expression correlate with poor prognosis 9 .
For families affected by TOC, these genetic discoveries enable DNA-based diagnosis rather than reliance solely on clinical symptoms. This is particularly valuable for identifying at-risk individuals before skin symptoms appear or before they develop esophageal cancer, allowing for early surveillance and intervention.
As one study noted, in families undergoing regular endoscopic surveillance, most esophageal cancers were detected at early stages, dramatically improving survival outcomes 5 .
The story of TOC research demonstrates how studying rare genetic disorders can yield insights with broad implications for understanding more common diseases. The identification of a novel RHBDF2 variant in an African family represents both a specific advancement in our understanding of this particular condition and a broader lesson about the importance of genetic diversity in medical research.
As science continues to unravel the molecular mechanisms connecting RHBDF2 mutations to esophageal cancer, we move closer to potential targeted therapies that might prevent or treat cancers in affected individuals. The ongoing research on TOC exemplifies the promise of personalized medicine—where understanding an individual's unique genetic makeup enables tailored screening, prevention, and treatment strategies.