According to some mythical stories, specific human characters had turned into trees. In our childhood, as we listened to the stories, we have imagined a ‘Treeman’ as a half-man, half-tree character. But now, we know the original scientific fact about a ‘TreeMan’ that it is not a fairytale, rather it is a rare, incurable, painful disease called Tree Man Syndrome; the medical world calls it Epidermodysplasia verruciformis (EV).
What is Tree Man Syndrome?
Epidermodysplasia verruciformis (EV) is a rare genetic inherited skin disorder caused by increased susceptibility to beta-papillomaviruses and characterized by a chronic eruption of brownish warts, scaly macules, and papules resembling tree bark, particularly on the hands and feet; hence the name referred to as ‘tree man’ syndrome.
This disease was first described in 1922 by two physicians Felix Lewandowsky and Wilhelm Lutz. That is why EV is also known as Lewandowsky-Lutz dysplasia. Dr. Lewandowsky passed away (1921) before the final documentation but he remained immortal through his discovery.
In the early stage of life, the symptoms of the disease appear with discoloration of the skin, or via the appearance of reddish, brown, or grey flat warts or macules on the exposed body parts, which are easily accessible for further viral contact and exposure to the sun.
Epidermodysplasia verruciformis is usually an autosomal recessive inherited skin disorder, which means, the affected person has gained two abnormal EV genes, one from each parent. Recessive trait develops only when both copies of the genes of homologous chromosomes are abnormal or mutated. Parents may not show any symptoms but carry the recessive mutant gene. Notably, the parents of about 10% of EV patients are blood relatives, which means the parents share a common ancestor.
EV is associated with a high risk of skin cancer. Warts or lesions usually start appearing from childhood and persist till death. About 8% of cases appear in infancy, 63% in the age group of 5-11 years, 24% in puberty, and the rest in adulthood. As the EV genes located in autosome, the disease affects both males and females and people of all human races. Besides depressed cellular immunity (genetic cause), individuals with acquired immunodeficiency syndrome (AIDS), stem cell or organ transplant recipients can be affected by EV more promptly.
Related Article: Pediatric Multisystem Inflammatory Syndrome related to COVID-19
Genetics Behind Epidermodysplasia verruciformis
Most cases of Epidermodysplasia verruciformis have explained as an autosomal recessive inheritance caused by mutations in the EVER1 and EVER2 genes located a little away from centromere in the long arm(q) of 17no. autosome in region 2, band 5. EVER1 and EVER2 genes on 17q25 locus often referred to as TMC6 and TMC8 genes (Transmembrane channel-like protein), respectively. The mutations decrease the cell’s capacity to fight against Human Papilloma Viruses. In some cases that lack this mutation, mutations in RAS homolog gene family member H (RHOH) located on autosome 4p14, MST1, and CORO1A have been found.
Here is a brief description of an example of mutation in the EVER2 gene:
EVER2 gene sample from a Chinese patient with EV showed a homozygous transition from cytosine to thymine at nucleotide position 568 within exon 6. This mutation led to a premature translation termination (R190X) as a result the predicted protein lacked 537 amino acids.
In 1985 one family with typical EV was described, in which only male members were affected. In that case study, the index patient’s ten children did not show any sign of EV, whereas, four of eight grandsons born to his daughters’ house had inherited the disorder. Surprisingly, no female members were affected. All the affected males were infected with HPV3 and HPV8. The inheritance in this family most likely resulted from an X- linked recessive genetic disorder.
So, it can be speculated that EV may result from defects in either of at least two different genetic loci, one of which is located on an autosome and another may be located on the X chromosome. The involvement of various genes in EV has made the classification of EV and EV-like syndromes complicated.
HOW GENE MUTATION INCREASE SUSCEPTIBITY TO HPV
One of the most common gene mutations implicated in Epidermodysplasia verruciformis is the mutation in EVER1/TMC6 and EVER2/TMC8 gene groups. TMC6 gene in human encodes Transmembrane Channel-like protein 6. TMC6 and its homolog TMC8, interact and form a complex with the Zinc Transporter 1 (ZNT1- encoded by SLC30A1 gene on chromosome 1) and localize mostly to the endoplasmic reticulum, but also to the Golgi apparatus and nuclear membrane. This complex regulates the distribution of zinc in the cell nuclei. Zn is an essential trace element for both innate and adaptive immune responses in human. Zn is also a necessary cofactor for many viral proteins, and the activity of the two gene complex appears to restrict the access of viral proteins to cellular zinc, hence limiting their growth.
So, the mutation in EVER1 and EVER2 results in the Zn deficiency which depresses both innate and adaptive immunity. Partial defects in cell-mediated immunity lead to an abnormal susceptibility of the infected individual to a specific group of HPV genotypes, generally known as EV-HPV.
These viruses cause an extra amount of keratin, a hard protein to develop in the top skin layer, representing the rough irregular hard texture of a wart. These warts continue to grow from the base and increase in size.
Different types of high-risk human papillomaviruses such as HPV types 5, 8, 10, and 47 with high oncogenic potential were detected by polymerase chain reaction (PCR) causing EV.
More than 90% of EV-associated skin cancer contains these virus types. The other group has low oncogenic potential and includes HPV types 14, 20, 21, 25, etc. These are mainly associated with benign skin lesions.
Related Article: Cancer Immunotherapy for Human Welfare
Development of Skin Cancer due to Tree Man Syndrome
The initial clinical diagnostic features of the Tree man syndrome are small pinkish/reddish-brown growths called papules which may be flat-topped or raised. Further, these small warts may become larger scaly inflamed patches of skin called plaques. In some specific body parts, such as hands and feet, the plaques further rise into tree-bark- like brownish growth called viral warts. Depending on the severity of human papillomavirus infection, viral warts continue to increase in size, lifelong.
In about 30%- 60% of EV patients the lesions have turned into nonmelanoma skin cancer on sun-exposed areas starting between the ages of 20 to 40 years. The lesions undergo malignant transformation into invasive squamous cell carcinomas. Exposure to sunlight or ultraviolet radiation increases the chance to convert a benign wart into malignant skin cancer.
Although these patients have depressed cellular immunity to HPV, they appear to have normal resistance to other pathogens.
Treatment of Tree Man Syndrome (EV disease)
Epidermodysplasia verruciformis is a lifelong disease and isn’t curable. No accurate treatment is available till today to prevent the formation of new lesions. Lesions can be treated or removed to give a patient temporary relief from pain. Recent overall treatment for EV involves medical and surgical treatments along with counseling and education to the patient.
Common treatment methods include:
|1. Treat and remove warts by chemical treatment, cryotherapy (use of extreme cold to freeze and remove abnormal tissue), electrosurgery (drying and burning off the wart by electrical charge), or by laser ablation (removal of damaged tissue by the laser beam).|
|2. Deep incision and surgical excision of thousands of lesions followed by skin grafting from other parts of the body.|
|3. One of the common experimental therapy is the implementation of intralesional interferon injection along with the application of isotretinoin and cholecalciferol analogs seems to be effective. Interferons are artificial proteins that strengthen the immune system and help to destroy viruses and prevent healthy cells from getting infected.|
|4. Oral medications, such as topical retinoids (isotretinoin and acitretin), fluorouracil, and imiquimod (these components have a higher rate of long-term clearance of lesions than cryotherapy) may be helpful. Zinc supplements can improve the clearance of warts.|
|5. Covering the sun-exposed body parts, especially if living at a high altitude or work outdoors, is advisable. Because sunlight increases the rate of EV lesions into skin cancer.|
Related Article: Pediatric Multisystem Inflammatory Syndrome related to COVID-19
IS TREE MAN SYNDROME CONTAGIOUS?
This syndrome is caused by abnormal susceptibility to some strains of human papillomaviruses. HPV is contagious and usually transmitted through skin-to-skin contact. But one can develop the symptoms only if he has a mutant gene or genes causing impaired immunity. As Tree Man Syndrome is a very rare disease, sufficient evidence in support of or against the contagious characteristics is not available.