Congenital Ichthyosiform Erythroderma (Nonbullous Congenital Ichthyosiform Erythroderma, Autosomal Recessive Congenital Ichthyosis)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Congenital ichthyosiform erythroderma (CIE) may present in the newborn period as a collodion baby (milder than with lamellar ichthyosis) with ectropion and eclabium (Figure 1). As the collodion membrane is shed, patients develop diffuse erythema and fine, powdery scaling and sometimes thickening of the palms and soles. Erythema tends to improve with age. Hypohidrosis and heat intolerance may be extreme.

Characteristic findings on physical examination

Physical examination shows diffuse erythema with fine, white scaling (Figure 2, Figure 3), although the extensor legs may have large, plate-like, brown scales (Figure 4). There is variable palmoplantar keratoderma, scarring alopecia, digit contracture, and ectropion. Short stature occurs in severe forms. Milder phenotypes have been described that fall into the category of CIE but are clinically intermediate between classic lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE). The new unifying nomenclature of ARCI (autosomal recessive congenital ichthyosis) is the most appropriate name for this whole family of conditions.

Expected results of diagnostic studies

Histopathology is not usually helpful in establishing a diagnosis and tends to show hyperkeratosis, and mild acanthosis with a normal or slightly thickened granular layer. A superficial dermal inflammatory infiltrate is more typical of CIE than LI but there are no distinct histopathologic differences between the two. Electron microscopy may show findings that suggest CIE but this test is not readily available to most practitioners. There are six known genes that lead to the CIE phenotype and commercial testing is available but expensive.

Diagnosis confirmation

The diagnosis of CIE is usually made on clinical grounds. The main differential diagnosis is LI and, given that they are caused by the same group of genetic defects, they may be a spectrum of disease rather than specific entities. Intermediate forms of CIE might be confused with ichthyosis vulgaris (autosomal dominant, flexural sparing, hyperlinear palms, decreased or absent granular layer), X-linked ichthyosis (only males, prolonged labor, sparing of palms, soles and flexures, comma-shaped corneal opacities, steroid sulfatase deficiency), bullous CIE (autosomal dominant, early blistering, warty scales and spiny ridges, odor), Sjögren-Larsson syndrome (mental retardation, spastic di-tetraplegia, atypical retinal pigmentation degeneration), and Netherton syndrome (severe eczema-like symptoms, abnormal hair showing trichorrhexis nodosa, high immunoglobulin E [IgE]).

Who is at Risk for Developing this Disease?

The incidence of CIE is about 1 in 180,000 births. Incidence is not affected by race, nationality or sex. Since the inheritance is autosomal recessive, there will be a one in four chance of a newborn having CIE if there is an affected sibling in the family.

What is the Cause of the Disease?

Etiology

CIE is inherited in an autosomal recessive fashion. Six genes have been isolated, TGM1 (the gene for transglutaminase-1), ABCA12, NIPAL4 (also known as ICHTHYIN), CYP4F22, ALOX12B, and ALOXE3. There is limited genotype-phenotype correlation in the group of autosomal recessive congenital ichthyoses, although classic LI is most closely associated with the gene for transglutaminase. Patients with a TGM1 mutation are more likely to have severe collodion membranes at birth, ectropion, alopecia, and large scales. About 20% of cases of ARCI have no currently identifiable gene abnormality, suggesting that there are other genes involved with this phenotype.

Pathophysiology

These genetic defects cause abnormalities in the quantity or quality of intercellular lamellar membranes, with resultant transepidermal water loss, epidermal hyperproliferation, and inflammation.

Systemic Implications and Complications

There are no systemic disorders directly associated with CIE. Collodion babies are at great risk of developing hypernatremic dehydration, temperature instability, sepsis, and constriction bands that might cause autoamputation. They should be monitored in a neonatal intensive care unit. Older children and adults may suffer from hypohidrosis and are at great risk of overheating. Avoiding heat and having a spray bottle on hand are important interventions.

Treatment Options

MEDICAL OPTIONS

Topical

-Education and psychological support

-Tubbing and gentle exfoliation, bath oils or sodium bicarbonate

-Bland emollients

-Eye lubrication

-Topical antibiotics for infection

-Keratolytic agents

-Topical retinoids

Systemic

-Oral retinoids

-Oral antibiotics for documented infection

SURGICAL/PHYSICAL OPTIONS

-Otolaryngology consultation for removal of ear canal scale and debris

-Ophthalmology consultation for appropriate eye lubrication and consideration of eyelid surgery

-Orthopedic or physical therapy consultation for digital contractures

Optimal Therapeutic Approach for this Disease

Hydration and soothing of the skin through bathing helps soften the stratum corneum and allows for GENTLE debridement of loose skin. A soft face cloth or an abrasive sponge (eg, loofah sponge) can facilitate this process. Scale removal may be aided with the addition of 1-2 handfuls of sodium bicarbonate in the bath tub, although some patients complain of stinging when this is done. Bath oils (eg, RoBathol) provide some comfort and emolliency, but care must be taken to avoid slipping. Bacterial overgrowth on dead skin and resultant odor can be ameliorated with antibacterial soaps or by adding a cup of bleach to a full adult tub.

Lubricating creams and ointments should be applied immediately after the tub, while still moist or after quickly dabbing dry. The choice of product depends on personal taste (a view of internet chat boards shows recommendations covering a wide spectrum) and preference but is preferably thick, fragrance- and chemical-free, and inexpensive. As such, plain petrolatum is a very nice choice. Less greasy creams may be preferred by the patient and some trial and error may be needed until a particular product is chosen. Some initial recommendations might be Cetaphil, CeraVe, Eucerin, or PDS creams, but patients and families quickly connect with other CIE families and share ideas. Additional applications through the course of the day are optimal but not always practical and patients may concentrate on exposed, visible areas of skin.

The scalp may need special care in loosening scale and providing lubrication. Overnight application of bland emollients or oils, preferably occluded by a shower cap or saran wrap, facilitates scale removal the following morning. P& S liquid is particularly helpful at loosening scale. Salicylic acid shampoos are helpful.

Eye lubrication is an important part of routine care, particularly if ectropion is present. Various over-the-counter products such as Artificial Tears, Tears Again, Clear Eyes Tears and many others are readily available. Patients should have regular ophthalmologic care.

Localized areas of superficial infection should be treated with mupirocin ointment. The routine daily use of topical antibiotics is not warranted. Cellulitis or widespread infection requires oral or intravenous antibiotics.

Various topical agents have keratolytic affects and are helpful in removing scale. Ammonium lactate (Lac Hydrin, AmLactin), urea (Ultra-Mide 25, Carmol 10 or 20), salicylic acid (Keralyt), and glycolic acid (Aqua Glycolic) are available in many prescription and over-the-counter products. Stinging may limit their use. Systemic absorption must be presumed when these products are used over large body surface areas, and there are reports of toxicity. Young children are at particular risk and salicylates, in particular, should not be used in infants or preschool aged children.

Response to topical retinoids is variable and irritation may result form their use. Tretinoin, Adapalene, and tazarotene have been tried with good results in some patients. Cost, irritancy, and potential systemic absorption limit the surface that can be treated so that use on just the face or other exposed areas is most practical. Adding an emollient over the top may help the irritancy. Tazarotene is a pregnancy category X medication.

The oral retinoids, isotretinoin and acitretin, have been used with some success in various ichthyotic conditions, especially LI but also CIE. Long-term doses of 0.5-1mg/kg/day of isotretinoin or 0.25-0.5mg/kg/day of acitretin are needed, but the effects are life altering for some patients who will wear shorts or a bathing suit for the first time in their life. Both medications are teratogenic, and isotretinoin is a better choice for females of childbearing potential due to its shorter half-life.

Mucous membrane dryness, joint aches, hair thinning, headaches, pseudotumor cerebri, lipid elevations, mood alterations, and bone changes are some other side effects. Laboratory monitoring of liver enzymes, lipids and pregnancy test for women is necessary. Periodic skeletal surveys consisting of a lateral view of the cervical and thoracic spin, a lateral view of the heel and a posteroanterior view of the pelvis should be done.

Patient Management

Most patients will not need regular monitoring and families will rapidly become more knowledgeable regarding the plethora of treatment options than their practitioners. Yearly or every other year visits are advised to monitor for any problems with growth and development, secondary infections, ectropion, ear canal build-up, or digital contractures. Referral to otolaryngology, ophthalmology, or orthopedics may be needed.

Genetic counseling should be offered to all patients and families. The risks associated with future pregnancies and the availability of genetic testing should be clearly and expertly explained. Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies can be performed but require prior identification of the disease-causing mutations in the family.

Special attention should be paid to the emotional well-being of the patient and family. Counseling should be offered as needed or appropriate. Support groups such as the Foundation for Ichthyosis and Related Skin Types (FIRST) offer patient/family conferences and multiple sources of information. Children may enjoy one of the several camps for children with chronic skin diseases offered by the American Academy of Dermatology.

Patients on systemic retinoids need regular laboratory and skeletal monitoring as above.

Unusual Clinical Scenarios to Consider in Patient Management

Collodion babies should be cared for in a neonatal intensive care unit. There is some mortality associated with this condition, which is exacerbated if skin care or monitoring for sepsis, dehydration, electrolyte imbalances, and nutrition are compromised. Thickened palms and soles will sometimes become secondarily infected with dermatophytes. A trial on an oral antifungal agent such as griseofulvin or terbinafine may result in some improvement.

What is the Evidence?

Akiyama , M, Sawamura , D, Shimizu. “the clinical spectrum of nonbullous congenital ichthyosiform erythroderma and lamellar ichthyosis”. Clin Exp Dermatol . vol. 28. 2003. pp. 235-40. (LI and CIE share common clinical, histologic, ultrastructural, and genetic features and may be part of a spectrum rather than distinct entities.)

DiGiovanna , JJ, Robinson-Bostom , L. “Ichthyosis. Etiology, diagnosis, and management”. Am J Clin Dermatol . vol. 4. 2003. pp. 81-95. (Overview of all ichthyoses with a good discussion of treatment options.)

Haenssle , HA, Finkenrath , A, Hausser , I, Oji , V, Traupe , H, hennies , HC. “Effective treatment of severe thermodysregulation by oral retinoids in a patient with recessive congenital lamellar ichthyosis”. Clin Exp Dermatol . vol. 33. 2008. pp. 578-81. (Case report and overview of oral retinoid treatment for ichthyosis with remarkable relief of hypohidrosis.)

Oji , V, Traupe , H. “Ichthyosis. Clinical manifestations and practical treatment options”. Am J Clin Dermatol . vol. 10. 2009. pp. 351-64. (Overview of all ichthyoses with a good discussion of treatment options.)

Oji , V, Traupe , H. “Ichthyosis: differential diagnosis and molecular genetics”. Eur J Dermatol . vol. 16. 2006. pp. 349-59. (Review of the ichthyoses, concentrating on diagnosis and the latest genetic findings.)

Oji , V, Tadini , G, Akiyama , M, Blanchet Bardon , C, Bodemer , C, Bourrat , E. “Revised nomenclature and classification of inherited ichthyoses: results of the first ichthyosis consensus conference in Soreze, 2009”. J Am Acad Dermatol . vol. 63. 2010. pp. 607-41. (New classification scheme for the ichthyoses emphasizing the use of autosomal recessive congenital ichthyosis (ARCI) as the most appropriate term to encompass lamellar ichthyosis and congenital ichthyosiform erythroderma.)

Vahlquist , A, Ganemo , A, Virtanen , M. “Congenital ichthyosis: an overview of current and emerging therapies”. Acta Derm Venereol . vol. 88. 2008. pp. 4-14. (Review of therapy for ichthyosis, including state-of-the-art therapies that are not yet available.)

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