Lamellar Ichthyosis 

Updated: Jun 28, 2017
Author: Chris G Adigun, MD, FAAD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Lamellar ichthyosis (LI) is an autosomal recessive disorder that is apparent at birth and is present throughout life. The newborn is born encased in a collodion membrane that sheds within 10-14 days. The shedding of the membrane reveals generalized scaling with variable redness of the skin. The scaling may be fine or platelike, resembling fish skin. Although the disorder is not life threatening, it is quite disfiguring and causes considerable psychological stress to affected patients.[1]

See the image below.

Collodion baby with translucent membrane of the bo Collodion baby with translucent membrane of the body.

Pathophysiology

Patients with lamellar ichthyosis have accelerated epidermal turnover with proliferative hyperkeratosis, in contrast to retention hyperkeratosis. This involves a mutation in the gene for transglutaminase 1 (TGM1). There are at least 14 identified different TGM1 mutations.[2] The transglutaminase 1 enzyme is involved in the formation of the cornified cell envelope. The formation of the cornified cell envelope is an essential scaffold upon which normal intercellular lipid layer formation in the stratum corneum occurs. Thus, mutations in the TGM1 secondarily cause defects in the intercellular lipid layers in the stratum corneum, leading to defective barrier function of the stratum corneum and to the ichthyotic phenotype seen in lamellar ichthyosis patients and in transglutaminase 1 knockout mice. How much a defective cornified cell envelope alone contributes to the barrier abnormality in ichthyoses remains unclear.[3]

To date, six genes for lamellar ichthyosis have been localized and 5 of them identified, as follows[4] :

  • TGM1 (14q11)

  • ABCA12 (2q34)

  • 19p12-q12

  • 19p13

  • ALOXE3-ALOX12B (17p13)

  • ichthyin (5q33)

Epidemiology

Frequency

Prevalence is less than 1 case per 300,000 individuals.

Race

Lamellar ichthyosis affects all populations.

Sex

Incidence in males and females is equal.

Age

The disease is present at birth and continues throughout life.

A rare phenotype of lamellar ichthyosis has been described in South Africa. The term bathing-suit ichthyosis describes the characteristic distribution of the lesions, which involve the trunk, the proximal parts of the upper limbs, the scalp, and the neck, with sparing of the central face and extremities. This form of lamellar ichthyosis is caused by a homozygous missense mutation in TGM1.[5, 6]

Prognosis

Patients with lamellar ichthyosis have normal life spans.

In the neonatal period, following the shedding of the collodion membrane, the newborn is at risk for secondary sepsis and hypernatremic dehydration.

As the child ages, the hyperkeratosis can interfere with normal sweat gland function, which can predispose to heat intolerance and possible heat shock. Ectropion may result in the inability to fully close the eyelids and can cause exposure keratitis.

External auditory canal stenosis and tympanic membrane blunting may result in a conductive hearing loss. Osseointegrated hearing devices may effectively bypass this hearing defect.

Less common associations include orthopedic abnormalities such as genu valgum, other ocular problems such as corneal perforation, and rickets.[7]

Like other ichthyoses, lamellar ichthyosis may be especially prone to widespread, severe, and chronic Trichophyton rubrum infections and viral infections.[4, 8, 9]

Patient Education

The family should be aware of these patient and family support groups:

  • Foundation for Ichthyosis and Related Skin Types (F.I.R.S.T), 2616 N. Broad Street, Colmar, PA 18915; telephone: (215) 997-9400, http://www.scalyskin.org, email: info@scalyskin.org.

  • National Registry for Ichthyosis and Related Disorders, University of Washington, Dermatology Department, Rm. BB1353, Box 356524, 1959 NE Pacific St., Seattle, WA 98195-6524; telephone: (206) 616-3179 or (800) 595-1265, email: info@skinregistry.org

 

Presentation

History

Lamellar ichthyosis presents at birth, typically with the newborn encased in a collodion membrane. The skin may be bright red, but progresses to develop large, platelike scales. The scales are large on the lower extremities, with the scales separated by superficial fissures. Although present at birth, during childhood and into adulthood, erythroderma is typically absent. Involvement of the acral surfaces can vary from mild hyperlinearity to severe hyperkeratosis of the palms and soles. The scalp may develop thick, adherent scale that may lead to scarring alopecia.[10] Nail dystrophy and thermoregulatory problems leading to possible seizures are also characteristics seen in lamellar ichthyosis.[11] Also notable are the consequences to the eyes, as ectropion formation is common.

Physical Examination

Newborn period

The newborn presents encased in a tough, filmlike membrane that fissures when stretched. This collodion membrane is shed by 10-14 days, revealing generalized erythema and scaling.

Childhood and adulthood

Skin

The disease is characterized by generalized scales, which range from fine and white to thick, dark, and platelike. The scales are arranged in a mosaic pattern resembling fish skin. The lesions involve the entire body and are increased in flexural surfaces such as the axilla, groin, antecubital fossa, and neck. The individual scales tend to be larger over the legs and, in some areas, are centrally attached and raised at the edges.[15] See the image below.

Keratoderma of the palms in a patient with lamella Keratoderma of the palms in a patient with lamellar ichthyosis. Courtesy of Dirk Elston, MD.

Nail abnormalities

These include secondary dystrophy with nail fold inflammation, subungual hyperkeratosis, and longitudinal or transverse stippling. The nails may grow 2-3 times the normal rate. See the image below.

Nail dystrophy and inflammation of the nail folds. Nail dystrophy and inflammation of the nail folds. Courtesy of M. Bryan, MD.

Scalp

Scarring alopecia can result from the overall tightness of skin and the thick stratum corneum entrapping hairs. The hair may be thin and fine but, similar to the nails, can grow at 2-3 times the normal rate.

Eyes

Patients may develop thick periocular scale that can lead to scarring ectropion formation. Ectropion formation impedes the lids from closing fully, causing chronic dry eyes that require treatment with artificial tears and other ophthalmic lubricants to prevent keratitis.

Other findings

The lips and mucous membranes tend to be spared. Other associated features are ectropion, eclabium, bilateral conjunctivitis, small and deformed ears, and inflexible digits due to taut skin. See the image below.

Inflexible fingers due to taut skin in a young pat Inflexible fingers due to taut skin in a young patient with lamellar ichthyosis. Courtesy of Dirk Elston, MD.

Causes

Lamellar ichthyosis is an autosomal recessive disorder in almost all cases. Genetic linkage studies have been performed on families with classic lamellar ichthyosis and show markers on band 14q11 in the region of the TGM1 gene locus. An autosomal dominant form of lamellar ichthyosis has been described.[12, 13] Paller et al concluded that the major orphan forms of ichthyosis share an interleukin 17–dominant immune fingerprint.[14]

Complications

Patients with lamellar ichthyosis have a normal life expectancy. Scaling of the skin may lead to obstruction of sweat glands, resulting in thermoregulatory complications. Bacterial colonization in areas of excessive scaling may lead to chronic ear infection. Nail dystrophy, ectropion formation, and scarring alopecia are other complications of lamellar ichthyosis.[11]

 

DDx

 

Workup

Approach Considerations

Genetic diagnosis and counseling of this disorder is imperative, and prenatal diagnosis for those at risk is encouraged. Genetic linkage studies have confirmed that mutations in TGM1, the gene encoding transglutaminase-1, is responsible for the development of this disorder.[10] Prenatal diagnosis is achieved through examination of the fetal skin by biopsy or amniotic fluid by electron microscopy. The expression and increased activity level of transglutaminase 1 is a key diagnostic tool.[11]

Laboratory Studies

As a result of the abnormal skin barrier, neonatal sepsis is a significant risk in the newborn period. If sepsis is considered, perform a sepsis workup. Chemistries and fluids need to be monitored closely because of the high incidence of hypernatremia observed.

Procedures

Skin biopsies can aid in the diagnosis of lamellar ichthyosis and detection of transglutaminase-1 expression. At birth, electron microscopy can be used to differentiate a severe collodion baby affected by lamellar ichthyosis from a baby affected by harlequin ichthyosis by demonstrating the absence of the marginal band.[16]

Histologic Findings

Skin biopsy results show a normal or thickened granular layer, mild-to-moderate hyperkeratosis with increased mitoses, and a perivascular lymphocytic infiltrate. In autosomal dominant lamellar ichthyosis, the stratum granulosum and stratum corneum are separated by a prominent transforming zone and scales contain elevated triglyceride and fatty acid levels, which aids in differentiation from autosomal recessive lamellar ichthyosis.

 

Treatment

Approach Considerations

Skin moisturizers are the main treatments for lamellar ichthyosis. Moisturizers serve as a barrier, and they also help in the removal of scales. Microfiber washcloths and urea also are used to remove the scales. For neonates, electrolytes should be monitored closely. The hyperkeratosis can interfere with sweat gland function, leading to disordered thermoregulation. Some patients may have severe heat intolerance. Oral retinoids are used for the purposes of speeding up epidermal turnover, and they can improve or prevent some of the consequences of the disease.[11] Oral retinoids may cause an increase in sweating, leading to improved heat tolerance. Oral retinoids may also decrease the thick periocular scale and decrease the propensity to develop ectropion. Artificial tears and eye lubricants are effective in patients with ectropion; surgery is suggested in those with severe disease.[17]

Transfer the newborn to the neonatal intensive care unit for close monitoring of fluids, electrolytes, and signs of sepsis and placement in a high-humidity incubator. Manual debridement of the collodion membrane is not recommended.

Surgery is occasionally necessary for severe ectropion, with skin grafts being the usual therapy. Inverting sutures may also stabilize the ectropion as the child grows, and it is surprisingly well tolerated.[18]

Consultations

Consult a dermatologist for the evaluation and treatment of the skin.

Consult an ophthalmologist for the evaluation and management of ectropion from birth.

Consult a genetics counselor for a discussion of the risks of subsequent children being affected. As with most genetic testing, prenatal diagnosis is controversial and can be a potential area for medicolegal problems. For severe congenital ichthyosis, as is the case with other genetic conditions, perhaps even earlier prenatal diagnosis by completely noninvasive analysis of DNA from fetal cells in maternal circulation, and preimplantation genetic diagnosis will be available in the future.[3]

Activity

A potential for heat intolerance and heat stroke is present; however, with proper counseling, activity does not need to be limited.

Prevention

Prenatal diagnosis is controversial. A fetal skin biopsy at 22 weeks may aid in prenatal diagnosis. In patients with a known gene locus, DNA linkage analysis may be useful.[19]

The quality of life of patients with the more severe congenital ichthyoses is often seriously affected and the parents' request for prenatal diagnosis is not easily ignored. Because of advances in the understanding of the causative genetic defects for severe congenital ichthyosis, making DNA-based prenatal diagnosis is now possible for several congenital ichthyosis, using chorionic villus or amniotic fluid sampling procedures early in pregnancy, with a lower risk to fetal health and with a reduced burden on the parents.[3]

 

Medication

Medication Summary

This disorder has no cure; therefore, treatment is directed at decreasing symptoms. This condition, along with the other congenital ichthyoses, is one of the targets in gene therapy research.

Emollients should be applied after showering or bathing. The stratum corneum can absorb 6 times its weight in water, and a heavy emollient, such as petrolatum jelly (Vaseline) or water-in-oil preparations (eg, Eucerin) should be applied while the skin is still wet. Alpha-hydroxy acids, such as lactic acid (eg, Lac-Hydrin), help reduce corneocyte adhesion and decrease the thickness of the epidermis. Urea creams can help soften scales. Salicylic acids in combination with propylene glycol help to remove dark scaling. Care must be taken when using topical salicylates over large areas, especially in children, because of reports of systemic salicylate intoxication. Topical retinoic acids (eg, Retin-A) decrease thickened scaling. Antiseptics and antimicrobials can be used topically to control odor. Because of the significant long-term adverse effects, reserve systemic retinoids for severe disease that is refractory to conventional therapy. Topical botanicals have been used, but more study is needed.[20]

Other therapies that have resulted in clinical improvement are Locobase fatty cream, which is 5% lactic acid and 20% propylene glycol in a lipophilic cream base[21] ; topical N -acetylcysteine, which has an antiproliferative effect[22, 23, 24] ; tazarotene topical 0.05%, a receptor-selective retinoid[25] ; and calcipotriol, a synthetic derivative of vitamin D-3.[26]

Oral liarozole (75-150 mg/day) was reported to help scaling and other symptoms but did not reach statistical significance because of the small sample size.[27]

Alternatively, ex vivo gene therapy has been reported for lamellar ichthyosis, with which normal gene expression of TGM1 has been restored and the phenotype correction was observed in engrafted lesional skin in vivo on the back of immunodeficient mice. Gene therapy serves to be a novel therapeutic approach to lamellar ichthyosis.[3]

Special medication considerations

Many of the medications used for lamellar ichthyosis have a long list of potential adverse effects, and care must be taken to discuss the advantages and disadvantages of treatment. Salicylate toxicity has been reported with systemic absorption of topical salicylic acids in the treatment of children with ichthyosis.[28] A case of lactic acidosis has been reported, with clinical signs of irritability, agitation, myoclonia, and difficulty walking, all which resolved upon discontinuation of the topical treatment.[29]

Topical tacrolimus, a macrolide immunosuppressant, should be used with caution because significantly elevated systemic tacrolimus levels have been reported in a patient with lamellar ichthyosis.[30]

Alpha-hydroxy acids

Class Summary

These agents decrease the thickness of the epidermis and reduce corneocyte adhesion.

Ammonium lactate (Lac-Hydrin)

Ammonium lactate relieves itching and aids healing of skin in mild eczemas and dermatoses, itching skin, minor wounds, and minor skin irritations. The formulation is 12% ammonium lactate in a base containing propylene glycol.

Topical retinoids

Class Summary

These agents appear to decrease the cohesiveness of follicular epithelial cells and stimulate mitotic activity, resulting in an increase in turnover of follicular epithelial cells.

Tretinoin topical (Retin-A, Avita)

Topical tretinoin inhibits microcomedo formation and eliminates lesions. It makes keratinocytes in sebaceous follicles less adherent and easier to remove. Use 0.01% gel.

Tazarotene (Tazorac)

Tazarotene is a topical gel 0.05%. It is a retinoid prodrug whose active metabolite modulates differentiation and proliferation of epithelial tissue; it may also have anti-inflammatory and immunomodulatory properties. Make sure skin is dry before applying gel.

Systemic retinoids

Class Summary

These agents inhibit sebaceous gland function and keratinization.

Isotretinoin (Accutane)

Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a synthetic 13-cis isomer of naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to vitamin A. Isotretinoin decreases sebaceous gland size and sebum production. It may inhibit sebaceous gland differentiation and abnormal keratinization.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

Acitretin (Soriatane)

Acitretin is a retinoic acid analog, similar to etretinate and isotretinoin. Etretinate is the main metabolite and has demonstrated clinical effects similar to those seen with etretinate. The mechanism of action is unknown.