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.
Collodion baby with translucent membrane of the body.
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. 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.
To date, six genes for lamellar ichthyosis have been localized and 5 of them identified, as follows :
Prevalence is less than 1 case per 300,000 individuals.
Lamellar ichthyosis affects all populations.
Incidence in males and females is equal.
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]
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.
Like other ichthyoses, lamellar ichthyosis may be especially prone to widespread, severe, and chronic Trichophyton rubrum infections and viral infections.[4, 8, 9]
The family should be aware of these patient and family support groups:
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.
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. See the image below.
Keratoderma of the palms in a patient with lamellar ichthyosis. Courtesy of Dirk Elston, MD.
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. Courtesy of M. Bryan, MD.
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.
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 patient with lamellar ichthyosis. Courtesy of Dirk Elston, MD.
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.
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.
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.
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.
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.
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.
A potential for heat intolerance and heat stroke is present; however, with proper counseling, activity does not need to be limited.
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.
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.
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.
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 ; topical N -acetylcysteine, which has an antiproliferative effect[19, 20, 21] ; tazarotene topical 0.05%, a receptor-selective retinoid ; and calcipotriol, a synthetic derivative of vitamin D-3.
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.
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.
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. 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.
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.
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.
These agents decrease the thickness of the epidermis and reduce corneocyte adhesion.
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.
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.
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.
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.
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.
These agents inhibit sebaceous gland function and keratinization.