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Keeping an eye on retinoids as treatment for the ectropion of lamellar ichthyosis

DII small banner By Warren R. Heymann, MD
Nov. 9, 2017

Clinical examples of autosomal recessive congenital ichthyosis: harlequin ichthyosis (HI) at birth (A); HI evolves into generalized exfoliating erythrodermic ichthyosis (B and C) (reprinted from “Menschen mit Ichthyose - ein Bildband 2003” courtesy of Selbsthilfe Ichthyose e. V.); collodion membrane with ectropion and eclabion in lamellar ichthyosis (LI) (courtesy of Dr Hagen Ott) (D); LI in childhood (E); LI caused by severe mutations in TGM1 in 79-year-old man (F); congenital ichthyosiform erythroderma (CIE) in early infancy (G); mild CIE in adult patient with ALOXE3 mutations (H); bathing suit ichthyosis represents LI variant characterized by localized healing of extremities (I).
Credit: JAAD

In patients afflicted with several variants of ichthyosis, ocular complications, such as ectropion, lagophthalmos (the inability to close the eyes completely), and exposure keratopathy can be observed. Ectropion is mostly associated with lamellar ichthyosis (LI). Cicatricial ectropion can be appreciated at birth (as in the case of Harlequin-type ichthyosis) or later in life. Symptoms may regress in the first months of life, or the intensity of the disease may progress with age. Corneal damage may be prevented by applying moisturizing agents consisting of artificial tears during the day, and by applying ointment into the conjunctivae, with taping the eyelids during sleep. Surgery may be required to correct the ectropion. (1)

LI falls under the umbrella of autosomal recessive congenital ichthyosis (ARCI). The diagnosis of nonsyndromic ARCI is established by skin findings at birth and in infancy. The 12 genes known to be associated with ARCI are ABCA12, ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, and TGM1; at least 15% of affected families do not have pathogenic variants in any of the known genes. A multigene panel is the diagnostic test of choice. If such testing is not available, single-gene testing can be considered starting with ABCA12 in individuals with harlequin ichthyosis, TGM1 for LI, and SLC27A4 in those presenting with the ichthyosis-prematurity syndrome. (2)
Standard medical management of ectropion due to LI, however, does not lead to significant and sustained improvement, nor does it prevent complications associated with chronic exposure of the cornea. (1) Any medical management that improves ocular disease would be most welcome. Systemic retinoids, usually isotretinoin, have been utilized effectively in severe cases of ARCI. What is the role of topical retinoids?

Retinoids have different receptor binding affinities to their target nuclear hormone receptors (retinoic acid receptors or retinoid X receptors) and cellular retinoic acid binding protein II (CRABP II); this variance is believed to account for differences in tolerability. The frequency of clinically significant irritation is low with all three available topical retinoids (tretinoin, adapalene, and tazarotene). Among studies with statistically significant results, adapalene gel 0.1% is the most tolerable retinoid followed by adapalene gel 0.3%. Tazarotene cream 0.1% and tretinoin 0.025% have comparable tolerability. (3) These tolerability studies are based on acne patients; I do not know if these results are transferable to those with ARCI.
The ectropion of LI presumably results from eyelid hyperkeratosis and, via drying and radial shrinkage of thickened stratum corneum, from subsequent increased tension on the lid margin and slightly increased weight. According to Craiglow et al, although ectropion characteristically improves beyond the neonatal period, it can persist throughout life, risking keratitis, conjunctivitis, and ephiphora. Many affected individuals are cosmetically displeased with their ectropion. Based on their prior experience of achieving good results with both tretinoin and tazarotene in a patient with LI, they reported the case of a 77-year-old woman with ARCI and longstanding bilateral lower eyelid ectropion. She had previously been followed by ophthalmology and treated with several topical therapies for exposure keratitis, subepithelial corneal scarring, and chronic punctate keratitis. At the time of presentation she was using loteprednol etabonate ophthalmic suspension, cyclosporine ophthalmic emulsion, and two varieties of artificial tears. She was considering surgical correction of the ectropion but was also interested in alternative treatment options. Tazarotene 0.1% cream daily to the bilateral lower eyelids was prescribed, which improved eye discomfort symptoms and degree of the ectropion within two weeks. Continued improvement in the ectropion and associated symptoms of eye irritation and dryness was noted at thirty months without any adverse effects. (4)
Hanson et al identified 5 children with LI and ectropion for whom tazarotene was prescribed. Patient age at the start of therapy ranged from 2 weeks to 9 years. Electronic medical records were reviewed and data from pediatric dermatologist and pediatric ophthalmologist visits were obtained. Data were collected before and after treatment of daily or twice-daily 0.05% to 0.1% tazarotene cream applied to the face and eyelids. All patients had improvement in the degree of ectropion, with complete resolution in two of the five patients. The two patients with lagophthalmos at the time of tazarotene initiation experienced complete resolution. No adverse effects were reported. The authors concluded that tazarotene cream appears to be effective in the management of ectropion and lagophthalmos in the setting of LI in children, even in the neonatal period. (5)

What is the status of using tretinoin or adapalene for ectropion secondary to LI? Although there is no specific reference, Craiglow et al (4) mentioned a patient treated with tretinoin (and tazarotene) that inspired their publication. Interestingly, Brodell et al reported the use of tretinoin causing an ectropion in two women who were utilizing it for photoaged skin (which resolved upon discontinuation of tretinoin). (6) To date, adapalene has not been reported to be used for LI, nor are there any reports of it being prescribed for ectropion; it has been beneficial for facial involvement in a patient with epidermolytic ichthyosis. (7)

Topical retinoids may smooth the future for patients with ARCI and ectropion — both literally and figuratively.

1. Zachara MG, et al. Surgical management of ichthyosis-related ectropion. Description of four cases and a literature review. J Plast Surg Hand Surg 2014; 48: 179-82.
2. Richard G. Autosomal recessive congenital ichthyosis. In Adam MP et al (eds) GeneReviews 2001 Jan 10 [updated 207 May 18]
3. Leyden J, et al. Why topical retinoids are mainstay of therapy for acne. Dermatol Ther (Heidelb) 2017; Jun 5 [Epub ahead of print]
4. Craiglow BG, et al. Topical tazarotene for the treatment of ectropion in ichthyosis. JAMA Dermatol 2013; 149: 598-600.
5. Hanson B, et al. Ectropion improvement with topical tazarotene in children with lamellar ichthyosis. Pediatr Dermatol 2017; 34: 584-9.
6. Brodell LP, et al. Reversible ectropion after long-term use of topical tretinoin on photodamaged skin. J Am Acad Dermatol 1992; 27:621-2.
7. Ogawa M, Akiyama M. Successful topical adapalene treatment for the facial lesions of an adolescent case of epidermolytic ichthyosis. J Am Acad Dermatol 2014; 71; e103-5.

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