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.

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.[1] 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.[2]

To date, 6 genes for lamellar ichthyosis have been localized and 5 of them identified, as follows[3] :

Epidemiology

Frequency

United States

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

Mortality/Morbidity

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.

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

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]

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.[7] 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.[8, 9]

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.[10]

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.[11]

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.[2]

Activity

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

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.

Newer 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[12] ; topical N -acetylcysteine, which has an antiproliferative effect[13, 14, 15] ; tazarotene topical 0.05%, a receptor-selective retinoid[16] ; and calcipotriol, a synthetic derivative of vitamin D-3.[17]

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.[18]

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.[2]

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.[19] 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.[20]

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.[21]

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.

Further Outpatient Care

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

Transfer

Transfer the newborn to the neonatal intensive care unit for close monitoring of fluids, electrolytes, and signs of sepsis. Manual debridement of the collodion membrane is not recommended.

Deterrence/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.[22]

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 the recent 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.[2]

Prognosis

Patients with lamellar ichthyosis have normal life spans.

Author

Heather Kiraly Orkwis, Philadelphia College of Osteopathic Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Jeffrey Meffert, MD, Assistant 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

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.

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.

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania

Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator; Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

References

  1. 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. Aug 22 2014;[View Abstract]
  2. Akiyama M, Shimizu H. An update on molecular aspects of the non-syndromic ichthyoses. Experimental Dermatology [serial online]. March 13, 2008;17:373-382. Available from: Medline. Accessed January 17, 2009. . Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0625.2007.00691.x/pdf[View Abstract]
  3. Oji V, Traupe H. Ichthyoses: differential diagnosis and molecular genetics. Eur J Dermatol. Jul-Aug 2006;16(4):349-59. [View Abstract]
  4. 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]
  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. Feb 2007;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. Nov-Dec 2005;15(6):433-6. [View Abstract]
  7. 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. Nov 21 2011;[View Abstract]
  8. Huber M, Rettler I, Bernasconi K, et al. Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science. Jan 27 1995;267(5197):525-8. [View Abstract]
  9. 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. Oct 13 2011;[View Abstract]
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  11. Sigurdsson H, Baldursson BT. Inverting Sutures With Systemic Retinoids and Lubrication Can Correct Ectropion in Ichthyosis. Ophthal Plast Reconstr Surg. Sep 11 2014;[View Abstract]
  12. Ganemo A, Virtanen M, Vahlquist A. Improved topical treatment of lamellar ichthyosis: a double-blind study of four different cream formulations. Br J Dermatol. Dec 1999;141(6):1027-32. [View Abstract]
  13. Davila-Seijo P, Flórez A, Davila-Pousa C, No N, Ferreira C, De la Torre C. Topical N-acetylcysteine for the treatment of lamellar ichthyosis: an improved formula. Pediatr Dermatol. May-Jun 2014;31(3):395-7. [View Abstract]
  14. Redondo P, Bauza A. Topical N-acetylcysteine for lamellar ichthyosis. Lancet. Nov 27 1999;354(9193):1880. [View Abstract]
  15. Bassotti A, Moreno S, Criado E. Successful treatment with topical N-acetylcysteine in urea in five children with congenital lamellar ichthyosis. Pediatr Dermatol. Jul-Aug 2011;28(4):451-5. [View Abstract]
  16. Stege H, Hofmann B, Ruzicka T, Lehmann P. Topical application of tazarotene in the treatment of nonerythrodermic lamellar ichthyosis. Arch Dermatol. May 1998;134(5):640. [View Abstract]
  17. 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. May 1995;131(5):556-60. [View Abstract]
  18. 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. Jan 2014;170(1):173-81. [View Abstract]
  19. Abdel-Magid EH, el-Awad Ahmed FR. Salicylate intoxication in an infant with ichthyosis transmitted through skin ointment--a case report. Pediatrics. Dec 1994;94(6 Pt 1):939-40. [View Abstract]
  20. Ramirez ME, Youseef WF, Romero RG, et al. Acute percutaneous lactic acid poisoning in a child. Pediatr Dermatol. May-Jun 2006;23(3):282-5. [View Abstract]
  21. Allen DM, Esterly NB. Significant systemic absorption of tacrolimus after topical application in a patient with lamellar ichthyosis. Arch Dermatol. Sep 2002;138(9):1259-60. [View Abstract]
  22. Basgul AY, Kavak ZN, Guducu N, Durukan B, Isci H. Prenatal diagnosis of congenital harlequin ichthyosis with 2D, 3D, and 4D ultrasonography. Clin Exp Obstet Gynecol. 2011;38(3):283-5. [View Abstract]
  23. DiGiovanna JJ. Ichthyosiform Dermatoses. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, Fitzpatrick TB, eds. Fitzpatrick's Dermatology in General Medicine. Vol 1. 5th ed. New York, NY: McGraw-Hill; 1999:587-8.
  24. Novice FM, Collison DW, Burgdorf WHC, Esterly N, eds. Lamellar ichthyosis. In: 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.