Lamellar Ichthyosis

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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.



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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] :

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:

Physical

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.[10] See the image below.



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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.



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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.

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.



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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.[11, 12] Paller et al concluded that the major orphan forms of ichthyosis share an interleukin 17–dominant immune fingerprint.[13]

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.[14]

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.

Medical Care

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.

Surgical Care

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.[15]

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.[16]

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 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.[17]

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[18] ; topical N -acetylcysteine, which has an antiproliferative effect[19, 20, 21] ; tazarotene topical 0.05%, a receptor-selective retinoid[22] ; and calcipotriol, a synthetic derivative of vitamin D-3.[23]

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.[24]

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]

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.[25] 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.[26]

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.[27]

Ammonium lactate (Lac-Hydrin)

Clinical Context:  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.

Class Summary

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

Tretinoin topical (Retin-A, Avita)

Clinical Context:  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)

Clinical Context:  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.

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.

Isotretinoin (Accutane)

Clinical Context:  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)

Clinical Context:  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.

Class Summary

These agents inhibit sebaceous gland function and keratinization.

Author

Heather Kiraly Orkwis, Philadelphia College of Osteopathic Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Jeffrey Meffert, MD, Associate Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Theresa Dressler Conologue, DO, FAAD, Physician, Department of Dermatology, Geisinger Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Daniel J Hogan, MD, Clinical Professor of Internal Medicine (Dermatology), Nova Southeastern University College of Osteopathic Medicine; Investigator, Hill Top Research, Florida Research Center

Disclosure: Nothing to disclose.

References

  1. Gul Z, Khan GA, Liaqat F, Muqarrab K. A New Born with Lamellar ichthyosis(Collodion Baby). J Coll Physicians Surg Pak. 2015 Aug. 25 (8):621-2. [View Abstract]
  2. Liu JJ, Yuan YY, Zhang XQ, Li ZM, Xu YS, Gao SM, et al. Mutations of transglutaminase-1 in Chinese patients with autosomal recessive congenital ichthyosis: a case report with clinical and genetic analysis of Chinese cases reported in literature. Clin Exp Dermatol. 2014 Aug 22. [View Abstract]
  3. Akiyama M, Shimizu H. An update on molecular aspects of the non-syndromic ichthyoses. Experimental Dermatology. March 13, 2008. 17:373-382. [View Abstract]
  4. Oji V, Traupe H. Ichthyoses: differential diagnosis and molecular genetics. Eur J Dermatol. 2006 Jul-Aug. 16(4):349-59. [View Abstract]
  5. Arita K, Jacyk WK, Wessagowit V, et al. The South African "bathing suit ichthyosis" is a form of lamellar ichthyosis caused by a homozygous missense mutation, p.R315L, in transglutaminase 1. J Invest Dermatol. 2007 Feb. 127(2):490-3. [View Abstract]
  6. Jacyk WK. Bathing-suit ichthyosis. A peculiar phenotype of lamellar ichthyosis in South African blacks. Eur J Dermatol. 2005 Nov-Dec. 15(6):433-6. [View Abstract]
  7. Angmo D, Patil B, Agarwal R, Mohanty K, Singh A. A Unique Case of JOAG With Lamellar Ichthyosis With Rickets: A Case Report and Review of the Literature. J Glaucoma. 2016 Mar. 25 (3):e280-3. [View Abstract]
  8. Scheers C, Andre J, Thompson C, Rebuffat E, Harag S, Kolivras A. Refractory Trichophyton rubrum infection in lamellar ichthyosis. Pediatr Dermatol. 2013. 30(6):e200-3. [View Abstract]
  9. Damsky WE, Leventhal JS, Khalil D, Vesely MD, Craiglow BG, Milstone LM, et al. Recurrent Coxsackievirus Infection in a Patient with Lamellar Ichthyosis. Pediatr Dermatol. 2016 Mar-Apr. 33 (2):e140-2. [View Abstract]
  10. Alavi A, Shahshahani MM, Klotzle B, Fan JB, Ronaghi M, Elahi E. Manifestation of diffuse yellowish keratoderma on the palms and soles in autosomal recessive congenital ichthyosis patients may be indicative of mutations in NIPAL4. J Dermatol. 2011 Nov 21. [View Abstract]
  11. Huber M, Rettler I, Bernasconi K, et al. Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science. 1995 Jan 27. 267(5197):525-8. [View Abstract]
  12. Hernández-Martín A, Garcia-Doval I, Aranegui B, de Unamuno P, Rodríguez-Pazos L, González-Enseñat MA, et al. Prevalence of autosomal recessive congenital ichthyosis: A population-based study using the capture-recapture method in Spain. J Am Acad Dermatol. 2011 Oct 13. [View Abstract]
  13. Paller AS, Renert-Yuval Y, Suprun M, Esaki H, Oliva M, Huynh TN, et al. An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis. J Allergy Clin Immunol. 2016 Aug 20. [View Abstract]
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  15. Sigurdsson H, Baldursson BT. Inverting Sutures With Systemic Retinoids and Lubrication Can Correct Ectropion in Ichthyosis. Ophthal Plast Reconstr Surg. 2014 Sep 11. [View Abstract]
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  17. Tirant M, Bayer P, Hercogovấ J, Fioranelli M, Gianfaldoni S, Chokoeva AA, et al. Treatment of ichthyosis lamellaris using a series of herbal skin care products family. J Biol Regul Homeost Agents. 2016 Apr-Jun. 30 (2 Suppl 3):65-72. [View Abstract]
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  22. Stege H, Hofmann B, Ruzicka T, Lehmann P. Topical application of tazarotene in the treatment of nonerythrodermic lamellar ichthyosis. Arch Dermatol. 1998 May. 134(5):640. [View Abstract]
  23. Kragballe K, Steijlen PM, Ibsen HH, et al. Efficacy, tolerability, and safety of calcipotriol ointment in disorders of keratinization. Results of a randomized, double-blind, vehicle-controlled, right/left comparative study. Arch Dermatol. 1995 May. 131(5):556-60. [View Abstract]
  24. Vahlquist A, Blockhuys S, Steijlen P, van Rossem K, Didona B, Blanco D, et al. Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double-blind, multinational, placebo-controlled phase II/III trial. Br J Dermatol. 2014 Jan. 170(1):173-81. [View Abstract]
  25. Abdel-Magid EH, el-Awad Ahmed FR. Salicylate intoxication in an infant with ichthyosis transmitted through skin ointment--a case report. Pediatrics. 1994 Dec. 94(6 Pt 1):939-40. [View Abstract]
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  29. Novice FM, Collison DW, Burgdorf WHC, Esterly N, eds. Lamellar ichthyosis. Handbook of Genetic Skin Disorders. Philadelphia, Pa: WB Saunders; 1994. 9-12.
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Collodion baby with translucent membrane of the body.

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

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

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

Collodion baby with translucent membrane of the body.

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

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

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