What are the other Names for this Condition? (Also known as/Synonyms)

• Familial Keratoderma with Carcinoma of the Esophagus
• Palmoplantar Keratoderma Associated with Esophageal Cancer
• Tylosis with Esophageal Cancer

What is Howel-Evans Syndrome? (Definition/Background Information)

• Howel-Evans Syndrome is an extremely rare form of hereditary focal palmoplantar keratoderma that is transmitted in an autosomal dominant manner. The condition manifests during early childhood and is associated with cancer of the esophagus (food-pipe). It is also known as Tylosis with Esophageal Cancer (or simply Tylosis)
• Hereditary focal palmoplantar keratoderma is a type of palmoplantar keratoderma (PPK) caused by genetic mutations. PPK is a benign skin condition, wherein there is thickening of skin (keratoderma) of the palms and/or soles. PPK is considered to be a pattern of skin findings and not a condition in itself. The abnormal skin thickening can be focal (localized), widespread (diffused), or punctate type (appearing as tiny bumps)
• There are two types of Howel-Evans Syndrome (Tylosis):
  • Type A Tylosis: It has a late-onset and is mostly associated with esophageal cancer
  • Type B Tylosis: It has an early onset and has usually a benign course (association with esophageal cancer is less often seen)
• A diagnosis of Howel-Evans Syndrome can be made by clinical (skin) exam and various other diagnostic tools including dermoscopy and wood’s lamp examination. The treatment for skin symptoms involves the use of moisturizers, topical creams, and skin softeners; the associated esophageal cancer may be managed using surgery, chemotherapy, and radiation therapy
• The prognosis of Howel-Evans Syndrome is determined on a case-by-case basis. In case of formation of esophageal cancer, the overall prognosis depends on several factors, including on the stage of the cancer

Who gets Howel-Evans Syndrome? (Age and Sex Distribution)

• Howel-Evans Syndrome is a highly uncommon congenital disorder that affects young children. It has an early onset or a late onset
  • An early onset is observed within the first 12 months of birth (Type B Tylosis)
  • A late onset is observed between ages 5 and 15 years (Type A Tylosis)
• The condition affects both males and females
• It is seen worldwide, and all racial and ethnic groups may be affected

What are the Risk Factors for Howel-Evans Syndrome? (Predisposing Factors)

• The risk factor for Howel-Evans Syndrome includes a positive family history of the condition
• Children born to consanguineous partners or spouses have a high risk for the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Howel-Evans Syndrome? (Etiology)

Howel-Evans Syndrome is caused by genetic abnormalities which are passed down (through families) in an autosomal dominant pattern. 

• The involved gene is RHBDF2 (of rhomboid protease family), located on chromosome 17q (long arm)
• Mutations on the gene result in abnormal regulation of epidermal growth factor receptor and inhibition of tumor necrosis factor (TNF-alpha)

Note: The gene may also play a role in the formation of stomach, ovary, and lung cancers, and several other abnormalities.

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Each child has the same 50 % chance of having the gene and being affected. Children, who do not inherit the abnormal gene, will not develop the condition, or pass it on to their offspring.

What are the Signs and Symptoms of Howel-Evans Syndrome?

In general, the signs and symptoms associated with Howel-Evans Syndrome may include:

• Appearance of localized/focal skin thickening in palms and soles during childhood
• The lesions are diffusely spread, yellowish, and appear like calluses (thick skin patches)
• The areas affected are normally pressure points, especially on the feet, such as the toe mounds and heel
• The condition may be painful in some individuals, particularly keratoderma on the feet
• The condition may be epidermolytic (causing damage to the epidermis), or non-epidermolytic
• Keratosis pilaris - dry rough patches on skin
• Fissures may form on skin
• Presence of white patches in the mouth (leukokeratosis, or oral leucoplakia affecting the gums)
• Decalcification of the maxillary teeth with loss of teeth

Additionally, the signs and symptoms of esophageal cancer may be noted.

How is Howel-Evans Syndrome Diagnosed?

The diagnosis of Howel-Evans Syndrome may involve:

• A complete evaluation of medical history along with a thorough examination of the skin lesions by a dermatologist
• The healthcare provider may also ask many questions related to the individual’s age, family medical history, current medications, cosmetics, body lotions used, other medical conditions, infections, etc.
• Blood tests that may include complete blood count (CBC) test, basic metabolic panel, and liver function test (LFT)
• Dermoscopy: It is a diagnostic tool where a dermatologist examines the skin using a special magnified lens
• Wood’s lamp examination: In this procedure, the healthcare provider examines the skin using ultraviolet light. It is performed to examine the change in skin pigmentation
• Imaging studies, which may include CT and MRI scans
• Molecular genetic testing to identify the gene involved
• Skin biopsy: A skin biopsy is performed and sent to a laboratory for a pathological examination. The pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Howel-Evans Syndrome?

The complications associated with Howel-Evans Syndrome may include:

• Emotional stress
• Cosmetic concerns
• Secondary infections
• Chronic rhinitis may be noted in some cases
• Chronic or relapsing lesions on lips
• Disruption of normal life and activities if the condition is severe
• Cancer of esophagus in mid to late adulthood; there is a very high risk of cancer development during one’s lifetime. It is reported that approximately 95% of the individuals develop esophageal cancer by age 65
• Lack of treatment response
• Treatment complications and medication side effects

How is Howel-Evans Syndrome Treated?

There is no cure for Howel-Evans Syndrome, and the condition is managed through symptomatic treatment (skin softening treatment), which may involve the following measures:

• Use of moisturizing creams and lotions; use of ointments containing vitamin D
• Use of oral and systemic retinoids
• Administration of keratolytics (topical medications containing salicylic acid, lactic acid, or urea)
• Phototherapy
• Surgical debridement (removal of thickened skin)

Mouth ulcers may be treated as follows:

• Surgical excision of the lesion
• Laser therapy to destroy the lesion
• Use of freezing temperatures to destroy cells in the plaque (cryotherapy)

In case of esophageal cancer development, the healthcare may treat the same using surgery, chemotherapy, and radiation therapy, based on evaluation of the cancer.

Regular follow up visits with the healthcare provider is important and recommended.

How can Howel-Evans Syndrome be Prevented?

Currently, Howel-Evans Syndrome is a genetic disorder that cannot be prevented. However, the following may be considered:

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited genetic disorders such as hereditary palmoplantar keratoderma

What is the Prognosis of Howel-Evans Syndrome? (Outcomes/Resolutions)

• The prognosis of Howel-Evans Syndrome may vary from one individual to another and is dependent on the severity of the condition
• In case of esophageal cancer development, the prognosis depends on the stage of cancer, and other parameters

Additional and Relevant Useful Information for Howel-Evans Syndrome:

Cleaning the skin too hard with strong chemicals or soaps may aggravate the skin condition. Care must be taken avoid strong soaps and chemicals that could potentially worsen the condition.