Usually, a common form of treatment for the condition is a type of hand cream which moisturises the hard skin. However, currently the condition is incurable.

Treatment of manifestations: special hair care products to help manage dry and sparse hair; wigs; artificial nails; emollients to relieve palmoplantar hyperkeratosis.

Oral retinoids have proven effective in treating this disorder. Depending on the side effects they may improve the quality of life. Examples are etretinate, acitretin, isotretinoin

Constant care is required to moisturise and protect the skin. The hard outer layer eventually peels off, leaving the vulnerable inner layers of the dermis exposed. Early complications result from infection due to fissuring of the hyperkeratotic plates and respiratory distress due to physical restriction of chest wall expansion.

Management includes supportive care and treatment of hyperkeratosis and skin barrier dysfunction. A humidified incubator is generally used. Intubation is often required until nares are patent. Nutritional support with tube feeds is essential until eclabium resolves and infants can begin nursing. Ophthalmology consultation is useful for the early management of ectropion, which is initially pronounced and resolves as scale is shed. Liberal application of petrolatum is needed multiple times a day. In addition, careful debridement of constrictive bands of hyperkeratosis should be performed to avoid digital ischemia. Cases of digital autoamputation or necrosis have been reported due to cutaneous constriction bands. Relaxation incisions have been used to prevent this morbid complication.

In the past, the disorder was nearly always fatal, whether due to dehydration, infection (sepsis), restricted breathing due to the plating, or other related causes. The most common cause of death was systemic infection and sufferers rarely survived for more than a few days. However, improved neonatal intensive care and early treatment with oral retinoids, such as the drug Isotretinoin (Isotrex), may improve survival. Early oral retinoid therapy has been shown to soften scales and encourage desquamation. After as little as two weeks of daily oral isotretinoin, fissures in the skin can heal, and plate-like scales can nearly resolve. Improvement in the eclabium and ectropion can also be seen in a matter of weeks. Children who survive the neonatal period usually evolve to a less severe phenotype, resembling a severe congenital ichthyosiform erythroderma. Patients continue to suffer from temperature dysregulation and may have heat and cold intolerance. Patients can also have generalized poor hair growth, scarring alopecia, contractures of digits, arthralgias, failure to thrive, hypothyroidism, and short stature. Some patients develop a rheumatoid factor-positive polyarthritis. Survivors can also develop fish-like scales and retention of a waxy, yellowish material in seborrheic areas, with ear adhered to the scalp.

The oldest known survivor is Nusrit "Nelly" Shaheen, who was born in 1984 and is in relatively good health as of April 2016. Lifespan limitations have not yet been determined with the new treatments.

A study published in 2011 in the Archives of Dermatology concluded, "Harlequin ichthyosis should be regarded as a severe chronic disease that is not invariably fatal. With improved neonatal care and probably the early introduction of oral retinoids, the number of survivors is increasing."

Gene therapy is really the only true therapy on the horizon for sufferers of EHK.

Over the past 10 years since the first EHK mouse model was developed, many ideas have been discussed about how best to cure EHK. Back as far as 1994 researchers were discussing new promising ideas such as topical lotions that would deliver ribozymes in a liposom cream. Ribozymes are a small piece of synthetic RNA which can digest RNA molecules. When cells make a protein from a gene on a chromosome sitting in the nucleus, the gene is first transcribed as a piece of RNA. This RNA is then translated into a protein. Ribozymes can be designed to destroy RNA molecules with specific sequences. In theory, this will stop the production of the protein encoded by the mutant alleles of the gene.

Successful gene therapy solutions have been recently achieved on mouse models by Jiang Chen M.D., a post-doctoral fellow in the laboratory of Dennis Roop, Ph.D., in the Center for Cutaneous Molecular Biology at Baylor College of Medicine. In 1998 they developed an inducible mouse model for epidermolysis hyperkeratosis which is viable, because the expression of a mutant K10 allele can be restricted to a focal area of the skin. "Once the mutant K10 allele is activated in epidermal stem cells by topical application of an inducer, these stem cells continuously give rise to defective progeny that form hyperkeratotic lesions which persist for the life of the mouse. It was observed that partial suppression of the mutant K10 gene may be sufficient to eliminate the disorder."

To test this observation, Dr. Chen and his team of researchers developed siRNAs that target the mutant K10 gene products for degradation, without affecting normal K10 gene products. Dr. Chen observed that under these conditions, an efficient knock-down of mutant, but not normal, K10 genes could be achieved. The results allowed the normal K10 genes to function properly building healthy skin tissues. He claims that these results may prove to be a very vital step forward in forging a novel gene therapy and possible permanent corrective therapy for this debilitating skin disorder.

A 1992 study of 163 affected persons found that most patients had no other medical problems and most manage to lead a relatively normal life.

There is no cure for IBS but in the future gene therapy may offer a cure.

Treatments for IBS generally attempt to improve the appearance of the skin and the comfort of the sufferer. This is done by exfoliating and increasing the moisture of the skin. Common treatments include:

- Emollients: moisturisers, petroleum jelly or other emolients are used, often several times a day, to increase the moisture of the skin.

- Baths: long baths (possibly including salt) several times a week are used to soften the skin and allow exfoliation.

- Exfoliating creams: creams containing keratolytics such as urea, salicylic acid and lactic acid may be useful.

- Antiseptic washes: antiseptics may be used to kill bacteria in the skin and prevent odour.

- Retenoids: very severe cases may use oral retinoids to control symptoms but these have many serious side effects including, in the case of IBS, increased blistering.

An extremely rare disease of which only a few isolated cases are known.

Meleda disease (MDM) or "mal de Meleda", also called Mljet disease, keratosis palmoplantaris and transgradiens of Siemens, (also known as "Acral keratoderma," "Mutilating palmoplantar keratoderma of the Gamborg-Nielsen type," "Palmoplantar ectodermal dysplasia type VIII", and "Palmoplantar keratoderma of the Norrbotten type") is an extremely rare autosomal recessive congenital skin disorder in which dry, thick patches of skin develop on the soles of the hands and feet, a condition known as palmoplantar hyperkeratosis.

Also known as ichthyosis hystrix gravior or porcupine man. This disease is characterised by spiny scales which cover the entire body except the face, genitals, palms and soles. The only known cases were in Edward Lambert (known as the porcupine man) who was exhibited in front of the Royal Society in London in 1731 and three generations of his descendants. No cases of this disease are now known though some experts believe that it may have been a type of epidermolytic hyperkeratosis. From the history of the Lambert family the disease appears to have been an autosomal dominant condition.

MDM is most common on the Dalmatian island of Mljet (or "Meleda"), thought to be because of a founder effect. It is of autosomal recessive inheritance. It may be caused by a mutation on the "SLURP1" gene, located on chromosome 8.

Palmoplantar keratodermas are a heterogeneous group of disorders characterized by abnormal thickening of the palms and soles.

Autosomal recessive and dominant, X-linked, and acquired forms have all been described.

Hairy palms and soles are both a type of cutaneous condition characterized by a hereditary hypertrichosis affecting the palms and soles. This condition is inherited in an autosomal dominant fashion.

Clouston's hidrotic ectodermal dysplasia (also known as "Alopecia congenita with keratosis palmoplantaris," "Clouston syndrome," "Fischer–Jacobsen–Clouston syndrome," "Hidrotic ectodermal dysplasia," "Keratosis palmaris with drumstick fingers," and "Palmoplantar keratoderma and clubbing") is caused by mutations in a connexin gene, GJB6 or connexin-30, characterized by scalp hair that is wiry, brittle, and pale, often associated with patchy alopecia.

Pachyonychia congenita may be divided into these types:

- Pachyonychia congenita type I (also known as "Jadassohn–Lewandowsky syndrome") is an autosomal dominant keratoderma that principally involves the plantar surfaces, but also with nails changes that may be evident at birth, but more commonly develop within the first few months of life.

- Pachyonychia congenita type II (also known as "Jackson–Lawler pachyonychia congenita" and "Jackson–Sertoli syndrome") is an autosomal dominant keratoderma presenting with a limited focal plantar keratoderma that may be very minor, with nails changes that may be evident at birth, but more commonly develop within the first few months of life.

Monilethrix (also referred to as beaded hair) is a rare autosomal dominant hair disease that results in short, fragile, broken hair that appears beaded. It comes from the Latin word for necklace ("monile") and the Greek word for hair ("thrix").

Treatment of choice for severe cases is oral retinoids. During flares, topical or oral antibiotics may be administered. Ciclosporin and prescription-only topical corticosteroids, e.g., betamethasone, have been used during acute flares. Some patients are able to prevent flares with use of topical sunscreens and oral vitamin C.

For minor forms, no specific treatment is required, but avoidance of excessive heat, humidity, stress and tight-fitting clothes is advised, as well as maintaining good hygiene. Topical creams (as above) are occasionally required to deal with flare-ups.

- benzoyl peroxide

- isotretinoin

- Topical Diclofenac Sodium

PPE invariably recurs with the resumption of chemotherapy. Long-term chemotherapy may also result in reversible palmoplantar keratoderma. Symptoms resolve 1–2 weeks after cessation of chemotherapy (Apisarnthanarax and Duvic 2003).

Naegeli–Franceschetti–Jadassohn syndrome (NFJS), also known as chromatophore nevus of Naegeli and Naegeli syndrome, is a rare autosomal dominant form of ectodermal dysplasia, characterized by reticular skin pigmentation, diminished function of the sweat glands, the absence of teeth and hyperkeratosis of the palms and soles. One of the most striking features is the absence of fingerprint lines on the fingers.

Naegeli syndrome is similar to dermatopathia pigmentosa reticularis, both of which are caused by a specific defect in the keratin 14 protein.

Isotretinoin, high doses of vitamin A and tretinoin cream can be utilized. Also, emollients, oral antihistamines, and antipruritic creams that contain menthol and camphor may be helpful because the lesions can become very itchy.

The best treatment for Kyrle's disease is to treat the underlying disease if present as life expectancy is also determined by the underlying disease. However, if there are no other diseases associated with Kyrle disease, treatment of the lesions is the course of action. There is a chance of the lesions healing without treatment but new ones will develop.

Recent research has used induced pluripotent stem cells to study disease mechanisms in humans, and discovered that the reprogramming of somatic cells restores telomere elongation in dyskeratosis congenita (DKC) cells despite the genetic lesions that affect telomerase. The reprogrammed DKC cells were able to overcome a critical limitation in TERC levels and restored function (telomere maintenance and self-renewal). Therapeutically, methods aimed at increasing TERC expression could prove beneficial in DKC.

Several medications can cause generalized or localized acquired hypertrichosis including:

Anticonvulsants: phenytoin

Immunosuppressants: cyclosporine

Vasodilators: diazoxide and minoxidil

Antibiotics: streptomycin

Diuretics: acetazolamide

Photosensitizes: Psoralen.

The acquired hypertrichosis is usually reversible once these medications are discontinued.

The main treatment for acral erythema is discontinuation of the offending drug, and symptomatic treatment to provide analgesia, lessen edema, and prevent superinfection. However, the treatment for the underlying cancer of the patient must not be neglected. Often, the discontinued drug can be substituted with another cancer drug or cancer treatment.

Symptomatic treatment can include wound care, elevation, and pain medication. Corticosteroids and pyridoxine have also been used to relieve symptoms. Other studies do not support the conclusion.

A number of additional remedies are listed in recent medical literature. Among them henna and 10% uridine ointment which went through clinical trial.

Acrokeratoelastoidosis of Costa (also known as "Keratoelastoidosis marginalis") is a familial condition characterized by multiple keratotic papules on the dorsum of the hands and feet, palms, soles, in which electron microscopy shows rarified, abnormal elastic tissue.

It was characterized in 1953.

Treatments such as liquid nitrogen, salicylic acid, tretinoin, and prednisone have been tried, though with limited success.