REVIEW

X-linked ichthyosis: An oculocutaneous genodermatosis

Neil F. Fernandes, MD,a Camila K. Janniger, MD,a,b and Robert A. Schwartz, MD, MPHa,b,c Newark, New Jersey
X-linked ichthyosis (XLI) is an X-linked recessive disorder of cutaneous keratinization with possible extracutaneous manifestations. It was rst described as a distinct type of ichthyosis in 1965. XLI is caused by a deciency in steroid sulfatase activity, which results in abnormal desquamation and a retention hyperkeratosis. XLI is usually evident during the rst few weeks of life as polygonal, loosely adherent translucent scales in a generalized distribution that desquamate widely. These are quickly replaced by large, dark brown, tightly adherent scales occurring primarily symmetrically on the extensor surfaces and the side of the trunk. In addition, extracutaneous manifestations such as corneal opacities, cryptorchidism, and abnormalities related to contiguous gene syndromes may be observed. Diagnosis of XLI is usually made clinically, as the histopathology is nonspecic, but conrmation may be obtained through either biochemical or genetic analysis. Treatment should focus on cutaneous hydration, lubrication, and keratolysis and includes topical moisturizers and topical retinoids ( J Am Acad Dermatol 2010;62:480-5.) Key words: genodermatosis; hyperkeratosis; ichthyosis; X-linked.

he term ichthyosis refers to a group of hereditary and acquired cutaneous disorders of keratinization. Ichthyosis is derived from the Greek root ichthys, which means sh in English.1 Ichthyosis is appropriately named, given that the skin of affected patients often resembles fish scales. This category of diseases was first described in 1808 by Robert Wilan,2 a physician to the London Dispensary.3 Ichthyosis was further studied and expanded to include a number of distinct diseases such as ichthyosis vulgaris, X-linked ichthyosis (XLI), lamellar ichthyosis, and epidermolytic hyperkeratosis. XLI specifically was first recognized by Wells and Kerr4 in 1965.

EPIDEMIOLOGY AND ORIGIN

XLI is a hereditary disorder of cutaneous keratinization, with possible extracutaneous manifestations, inherited in an X-linked recessive fashion. It is the second most common type of ichthyosis, with a prevalence of 1 in 6000, affecting almost exclusively
From Dermatology,a Pediatrics,b and Pathology,c New Jersey Medical School. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Robert A. Schwartz, MD, MPH, Dermatology, New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103. E-mail: roschwar@cal.berkeley.edu. Published online January 18, 2010. 0190-9622/$36.00 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.04.028

males.5 XLI has rarely been described in homozygous women who were offspring of an affected man and a female carrier.6,7 There is no noticeable racial or geographic predilection.8 XLI is most commonly caused by a genetic defect leading to a deciency of the enzyme steroid sulfatase (STS), also known as arylsulfatase C.9-11 A small number of cases may be the consequence of other genetic alterations of the X chromosome not directly linked to the Sts gene.12 The gene coding for STS has been mapped to the short arm of the X chromosome at Xp22.3.13,14 This region of the X chromosome escapes normal inactivation, so female carriers cannot develop XLI through functional mosaicism.15 Approximately 80% to 90% of cases of XLI are a result of complete deletions of the 146-kilobase gene.16 STS catalyzes the hydrolysis of aryl and alkyl steroid sulfates such as dehydroepiandrosterone sulfate, cholesterol sulfate, pregnenolone sulfate, and androstenediol-3-sulfate to produce biologically active steroids.16,17 Beyond the skin, STS has a wide variety of physiologic functions in the breast, immune system, brain, reproductive tract, osteoblasts, leukocytes, and thrombocytes.16

PATHOPHYSIOLOGY
STS is normally found within the epidermis and is thought to play a role in active cutaneous steroid production and lipid regulation.16 Lipids normally make up 11% of the epidermis; 10% of these lipids are sterols such as cholesterol sulfate, which is the

480

J AM ACAD DERMATOL
VOLUME 62, NUMBER 3

Fernandes, Janniger, and Schwartz 481

substrate for STS.8,18 Physiologic breakdown of XLI, normally appearing during adolescence or early cholesterol sulfate leads to corneodesmosome degadulthood.8 These asymptomatic fine, flourlike 19 radation and normal desquamation. A deficiency opacities can be seen in between 10% to 50% of of STS results in the accumulation of cholesterol patients diffusely deposited in the posterior corneal sulfate in the membranes of stratum corneum cells.20 stroma or Descemet membrane.29-31 These corneal Cholesterol sulfate is thought to play a role in opacities may present in 25% of female carriers as, membrane integrity and normal desquamation interestingly enough, the only finding related to within the stratum corneum. XLI.30 Although they almost never affect visual acuity in Therefore, a pathological inCAPSULE SUMMARY and of themselves, they may crease in quantity of choleslead to recurrent corneal terol sulfate results in X-linked ichthyosis is an X-linked erosions.26 increased intracellular stabilrecessive disorder of keratinization 18 Cryptorchidism is another ity and cohesion. The end caused by a deficiency in steroid result is partial retention extracutaneous nding, ocsulfatase activity. hyperkeratosis with a phenocurring in approximately 21 Mild scaling in the first few days of life type of excess scaling. 20% of those with XLI.32 evolves to prominent brownish, There is also an increased polygonal, firmly adherent scales. risk of testicular germ cell CLINICAL FEATURES cancer with XLI, which is The rst manifestation of Corneal opacities, cryptorchidism, and independent of testicular XLI may be delayed or proother abnormalities may be evident. maldescent.33,34 It is unclear longed labor in mothers of Diagnosis is clinical and is confirmed by whether the increased risk of affected fetuses as a result of biochemical or genetic analysis. cryptorchidism in XLI is the absence of STS in the fetal caused by the deficiency of placenta, leading to deSTS or concurrent mutations in nearby genes of the X creased levels of estrogen and insufcient dilation chromosome involved in testicular descent.35 of the cervix.22,23 XLI, however, is not usually However, patients have been shown to have normal detected until the first few weeks of life when testosterone levels, sexual development, and polygonal, loosely adherent translucent scales begin fertility.11 to appear in a generalized distribution and desqua24 Neurologic ndings may also be found in patients mate widely. They quickly develop into large, dark with XLI, often occurring as manifestations of conbrown, tightly adherent scales occurring primarily on tiguous gene syndromes. These abnormalities inthe extensor surfaces and the side of the trunk clude epilepsy with electroencephalographic symmetrically (Figs 1 and 2). These scales are often ndings, mental retardation, and hyposmia.36 Other noted by the casual observer to look similar to the general alterations have rarely been described in scales of a fish and to have a dirty appearance. patients with XLI. These findings include pyloric Initially the skin on the scalp, preauricular surfaces, hypertrophy, congenital defect of the abdominal and neck is almost always affected, but scales in this wall, acute lymphoblastic leukemia, bilateral peridistribution tend to largely disappear throughout ventricular nodular heterotopia, and end-stage renal childhood.8 Consequently lower extremity alterafailure.36-39 Contiguous gene involvement in patients tions tend to be more prominent in patients after with XLI can result in a variety of syndromes includearly childhood. Flexural surfaces are often affected, ing Rud syndrome, Conradi syndrome, and whereas the palms, soles, hair, and nails are usually Kallmann syndrome.36 Patients with Rud syndrome spared.8 Patients with XLI also have decreased exhibit cryptorchidism, retinitis pigmentosa, mental numbers of sweat glands and, hence, a reduction retardation, and epilepsy.40 Shortening of the limbs, in sweat production.25 epiphyseal stippling, craniofacial defects, short statExtracutaneous ndings are common in patients ure, and chondrodysplasia punctata are all features with XLI as well (Table I). Ocular abnormalities are of Conradi syndrome.41 Kallmann syndrome is hyseen frequently in the ichthyoses in general. These pogonadotropic hypogonadism with associated include asymptomatic irregularities of the eyelids, anosmia. conjunctiva, cornea, lens, and fundus.26 Ocular findings may occur in isolation or as part of DIAGNOSIS ichthyosis-related syndromes such as keratitis-ichThe diagnosis of XLI may be suggested during the thyosis-deafness syndrome and ichthyosis-folliculaprenatal course after a careful family history. History ris-alopecia-photophobia syndrome.27,28 Corneal of a skin disease with signicant scaling present in opacities are the most common alteration seen in
d d d d

482 Fernandes, Janniger, and Schwartz

J AM ACAD DERMATOL
MARCH 2010

Table I. Extracutaneous manifestations of X-linked ichthyosis

Ocular Genitourinary Orthopedic Neurologic Corneal opacities (10%-50%) Cryptorchidism (20%), germ cell testicular cancer Chondrodysplasia punctata Mental retardation, epilepsy

Fig 1. Patient with X-linked ichthyosis with characteristic large, dark brown, tightly adherent scales across his entire back.

Fig 2. Patient with X-linked ichthyosis with characteristic large, dark brown, tightly adherent scales along extensor surfaces of his upper extremities.

only the male relatives of the mother should arouse suspicion. If low to absent levels of estriol are detected during the triple screen for alpha fetoprotein, human chorionic gonadotropin, and estriol during the second trimester, this should alert the physician to the possibility of XLI in the fetus.42 A birth history involving a prolonged or complicated labor provides pertinent information as well. After birth, a complete history and physical examination aids largely in the identification of XLI. The time course of the presentation is important, remembering that 3 of 4 patients experience scaling by 1 week of life.21 Drawing the family pedigree may elucidate the mode of inheritance. Special attention should be

paid to the distribution, quality, and quantity of any scaling.22 An eye examination demonstrating comma-shaped opacities of the posterior capsule can also be quite useful in terms of supporting the correct diagnosis.22 The diagnosis of XLI may be conrmed through biochemical or genetic analysis. Prenatal identication can be made by detecting decreased estrogen levels and the presence of nonhydrolyzed sulfated steroids in maternal urine.38 If the genetic defect of the Sts gene in the family is known, Southern blot, fluorescent in situ hybridization, or polymerase chain reaction can be performed on chorionic villi or amniotic fluid samples.43 The diagnosis of XLI is usually confirmed biochemically or genetically after birth, however. Serum protein electrophoresis may be performed to show increased mobility of the betalipoprotein fraction as a result of elevated serum cholesterol sulfate levels.21 Direct biochemical techniques can be used to demonstrate deficiency of STS activity in skin fibroblasts, leukocytes, and keratinocytes.8 Southern blot, fluorescent in situ hybridization, and polymerase chain reaction are current methods for confirming a causative mutation for XLI. Sts gene deletions can be identified through these techniques, but the few cases caused by point mutations instead of deletions can be missed.44-46 Skin biopsy for histopathology is generally not useful in conrming a diagnosis of XLI because microscopic changes are often subtle and nonspecic. Affected skin may appear normal or resemble skin affected by ichthyosis vulgaris.21 One sees hyperkeratosis with varying degrees of hypergranulosis in the epidermis (Fig 3).22 The dermis usually exhibits edema with mild perivascular inflammation.8 However, a biopsy specimen may be beneficial in considering other conditions with specific histopathologic features in the differential diagnosis of XLI.

DIFFERENTIAL DIAGNOSIS
XLI may require distinction from atopic dermatitis and other ichthyoses, most notably ichthyosis vulgaris and lamellar ichthyosis. Ichthyosis vulgaris is the most difcult to differentiate from XLI, and can be hereditary or acquired.47 Ichthyosis vulgaris

J AM ACAD DERMATOL
VOLUME 62, NUMBER 3

Fernandes, Janniger, and Schwartz 483

Fig 3. Histopathological picture of X-linked ichthyosis exhibiting subtle hyperkeratosis and hypergranulosis with mild dermal perivascular inammation (Hematoxylineosin stain; original magnication: 3100.)

is associated with follicular keratosis and symmetric, light gray scaling that appears after 3 months of life.1 Flexural surfaces are usually spared, as opposed to XLI, in which flexural surfaces are often affected.8 The histopathology of ichthyosis vulgaris may appear similar to that of XLI. Biopsy specimen generally shows basket-weave hyperkeratosis in the stratum corneum, patchy parakeratosis, a markedly decreased granular cell layer, and perivascular lymphohistiocytic infiltration of the dermis.1 Hereditary ichthyosis vulgaris can be differentiated from XLI because it is inherited in an autosomaldominant manner. Acquired ichthyosis, on the other hand, is found almost exclusively in adults and is considered a marker for cancer, infection, or other serious systemic illnesses.48 Despite clinical similarities between the two, XLI can ultimately be differentiated from ichthyosis vulgaris, and other cutaneous diseases, by demonstrating a deficiency of STS.

MANAGEMENT
XLI is an incurable lifelong condition that rarely affects normal life functions.49 Most patients with XLI have disease limited to the skin. The majority of cases improve with age and do not require treatment.8 Cutaneous symptoms are naturally alleviated during summer months as well. However, some patients with XLI and other types of ichthyoses experience a significantly reduced quality of life. A 2004 Swedish study showed that patients with XLI have a lower health-related quality of life as evidenced by their responses to the Dermatology Life Quality Index and Standard Form 36 questionnaires.50 Therefore, lifestyle modifications and pharmacologic therapies

should be prescribed when indicated to modulate the abnormal keratinization by aiding in the shedding of excess scale and blocking excessive keratinization.8 Once the disease is recognized, one should initiate topical therapy: cutaneous hydration, lubrication, and keratolysis.22 One option for treatment of XLI is to wear a plastic pajama suit overnight after applying 40% to 60% propylene glycol in water to the entire body every night until excess scales are eliminated.51 Therapy then can be gradually weaned until once-aweek use of the suit maintains clear skin.51 If the patient is unable to tolerate this therapy, other measures can be taken to focus on hydration. Humidifying the home, school, and other environments during cold winter months often proves beneficial.22 Bathing etiquette is important as well. Soaking for prolonged periods and mechanical debridement with a roughly textured sponge should be encouraged, and lubricating bath oils followed by application of creams and ointments after the bath, while the skin is still wet, is useful.22 Topical keratolytics should be used as well. Formulations that include lactic acid, glycolic acid, salicylic acid in concentrations of 0.5% to 60%, and urea in concentrations of 5% to 10% may be used.22 Goldsmith and Baden52 reported uniformly excellent results after treating 10 patients with XLI with propylene glycol in aqueous concentrations of 40% to 60%. Lykkesfeldt and Hyer53 showed a good response to 10% cholesterol cream in 18 of 20 patients with XLI treated and demonstrated that it was superior to urea cream in most cases. Combination therapy with an alpha-hydroxy acid and cholesterol cream may be an excellent option.54 In neonates and infants, however, topical keratolytics should be used with considerable caution because their immature skin barrier function and increased body surface area to weight ratio may lead to increased percutaneous absorption and systemic toxicity.55 Retinoic acid derivatives such as topical isotretinoin have also been shown to have considerable success in treating patients with XLI.56,57 Frost and Weinstein,58 in an early study, demonstrated a better response in 6 of 8 patients with XLI treated with vitamin-A acid versus placebo. A short-term paired comparison on two patients with XLI suggested 0.1% tretinoin cream was superior to 0.1% topical tretinoin cream.59 Hofmann et al60 recently demonstrated superior efficacy of the receptor-selective retinoid tazarotene at 0.05% concentration in the treatment of 4 patients with XLI. Systemic absorption of this agent when used topically for ichthyoses has since been shown to be minimal.61 Although it has not been effectively implemented as of yet, research is

484 Fernandes, Janniger, and Schwartz

J AM ACAD DERMATOL
MARCH 2010

underway regarding the possibility of using gene transfer to treat XLI.62,63 Collaboration with other specialists may be helpful in successfully treating patients with XLI. Patients and their families should be referred for genetic counseling to receive further education regarding XLI and its inheritance pattern. Potential risk in future pregnancies should be emphasized as well, and the obstetrician should be involved in this aspect of management. In addition, patients should be advised to perform regular testicular self-examinations, given the increased risk of testicular germ cell cancer in XLI. Physicians should also consider including testicular evaluation as part of the physical examination of these patients.
REFERENCES 1. Okulicz JF, Schwartz RA. Hereditary and acquired ichthyosis vulgaris. Int J Dermatol 2003;42:95-8. 2. Wilan R. Ichthyosis. In: On cutaneous diseases. Vol 1. London: Barnard; 1808: 197-212. 3. Shwayder T, Ott F. All about ichthyosis. Pediatr Clin North Am 1991;38:835-57. 4. Wells RS, Kerr CB. Genetic classification of ichthyosis. Arch Dermatol 1965;92:1-6. 5. Wells RS, Kerr CB. Clinical features of autosomal dominant and sex-linked ichthyosis in an English population. Br Med J 1966; 1:947-50. ller CR, Ropers HH. X-linked recessive 6. Mevorah B, Frenk E, Mu ichthyosis in three sisters: evidence for homozygosity. Br J Dermatol 1981;105:711-7. 7. Thauvin-Robinet C, Lambert D, Vaillant G, Caillier P, Donzel A, Cusin V, et al. X-linked recessive ichthyosis in a girl: strategy for identifying the causal mechanism. Br J Dermatol 2005;152:191-3. ndez-Mart lez-Sarmiento R, De Unamuno P. n A, Gonza 8. Herna X-linked ichthyosis: an update. Br J Dermatol 1999;141:617-27. -Ilsen A, Koppe JG, Jo bsis AC, de Groot WP. Enzy9. Marinkovic matic basis of typical X-linked ichthyosis. Lancet 1978;2:1097. 10. Shapiro LJ, Weiss R, Buxman MM, Vidgoff J, Dimond RL, Roller JA, et al. Enzymatic basis of typical X-linked ichthyosis. Lancet 1978;2:756-7. 11. Nussbaumer P, Billich A. Steroid sulfatase inhibitors. Med Res Rev 2004;24:529-76. 12. Robledo R, Melis P, Schillinger E, Casciano I, Balazs I, Rinaldi A, et al. X-linked ichthyosis without STS deficiency: clinical, genetical, and molecular studies. Am J Med Genet 1995;59:143-8. 13. Mohandas T, Shapiro LJ, Sparkes R, Sparkes MC. Regional assignment of the steroid sulfatase X-linked ichthyosis locus: implications for a non-inactivated region on the short arm of the human X chromosome. Proc Natl Acad Sci U S A 1979;76: 5779-83. 14. Tiepolo L, Zuffardi O, Fraccaro M, di Natale D, Gargantini L, ller CR, et al. Assignment by deletion mapping of the Mu steroid sulfatase X-linked ichthyosis locus to Xp223. Hum Genet 1980;54:205-6. 15. Siegel DH, Sybert VP. Mosaicism in genetic skin disorders. Pediatr Dermatol 2006;23:87-92. 16. Reed MJ, Purohit A, Woo LW, Newman SP, Potter BV. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev 2005;26:171-202. 17. Unamuno P, Santos C. Diagnostico de laboratorio de la ictiosis X. Piel 1991;6:80-3.

18. Williams ML. Epidermal lipids and scaling diseases of the skin. Semin Dermatol 1992;11:169-75. 19. Elias PM, Crumrine D, Rassner U, Hachem JP, Menon GK, Man W, et al. Basis for abnormal desquamation and permeability barrier dysfunction in RXLI. J Invest Dermatol 2004;122:314-9. 20. Williams ML, Elias PM. Stratum corneum lipids in disorders of cornification: increased cholesterol sulfate content of stratum corneum in recessive x-linked ichthyosis. J Clin Invest 1981;68: 1404-10. 21. Shwayder T. Disorders of keratinization: diagnosis and management. Am J Clin Dermatol 2004;5:17-29. 22. DiGiovanna JJ, Robinson-Bostom L. Ichthyosis: etiology, diagnosis, and management. Am J Clin Dermatol 2003;4:81-95. 23. Bradshaw KD, Carr BR. Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis. Obstet Gynecol Surv 1986;41:401-13. 24. Hazan C, Orlow SJ, Schaffer JV. X-linked recessive ichthyosis. Dermatol Online J 2005;11:12. 25. Delfino M, De Ritis G, Fabbrocini G, Procaccini EM, Illiano GM, Piccirillo A. Sweat gland function in patients with X-linked ichthyosis. Recenti Prog Med 1991;82:677-8. 26. Jay B, Blach RK, Wells RS. Ocular manifestations of ichthyosis. Br J Ophthalmol 1968;52:217-26. 27. Messmer EM, Kenyon KR, Rittinger O, Janecke AR, Kampik A. Ocular manifestations of keratitis-ichthyosis-deafness (KID) syndrome. Ophthalmology 2005;112:e1-6. garbane H, Me garbane A. Ocular 28. Traboulsi E, Waked N, Me findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome. Ophthalmic Genet 2004;25:153-6. 29. Haritoglou C, Ugele B, Kenyon KR, Kampik A. Corneal manifestations of X-linked ichthyosis in two brothers. Cornea 2000; 19:861-3. 30. Costagliola C, Fabbrocini G, Illiano GM, Scibelli G, Delfino M. Ocular findings in X-linked ichthyosis: a survey on 38 cases. Ophthalmologica 1991;202:152-5. 31. Piccirillo A, Auricchio L, Fabbrocini G, Parenti G, Ballabio A, Delfino M. Ocular findings and skin histology in a group of patients with X-linked ichthyosis. Br J Dermatol 1988;119:185-8. 32. Traupe H. The ichthyoses: a guide to clinical diagnosis, genetic counseling, and therapy. Berlin: Springer-Verlag; 1989. 33. von Eyben FE. Chromosomes, genes, and development of testicular germ cell tumors. Cancer Genet Cytogenet 2004;151:93-138. 34. Lykkesfeldt G, Hyer H, Lykkesfeldt AE, Skakkebaek NE. Steroid sulphatase deficiency associated with testis cancer. Lancet 1983;2:1456. 35. Traupe H, Happle R. Mechanisms in the association of cryptorchidism and X-linked recessive ichthyosis. Dermatologica 1986;172:327-8. 36. Ozawa H, Osawa M, Nagai T, Sakura N. Steroid sulfatase deficiency with bilateral periventricular nodular heterotopia. Pediatr Neurol 2006;34:239-41. 37. Mallory SB, Kletzel M, Turley CP. X-linked ichthyosis with acute lymphoblastic leukemia. Arch Dermatol 1988;124:22-4. 38. Richard G. Molecular genetics of the ichthyoses. Am J Med Genet C Semin Med Genet 2004;131C:32-44. 39. Matsukura H, Fuchizawa T, Ohtsuki A, Higashiyama H, Higuchi O, Higuchi A, et al. End-stage renal failure in a child with X-linked ichthyosis. Pediatr Nephrol 2003;18:297-300. 40. Rud E. Et Tilflde af Infantilismus med Tetani, Epilepsy, Polyneuritis, Ichtiosis og Anmia af Pernicios type. Hospitalstidende 1927;70:525-38. 41. Curry CJ, Magenis RE, Brown M, Lanman JT Jr, Tsai J, OLague P, et al. Inherited chondrodysplasia punctata due to a deletion of the terminal short arm of an X chromosome. N Engl J Med 1984;311:1010-5.

J AM ACAD DERMATOL
VOLUME 62, NUMBER 3

Fernandes, Janniger, and Schwartz 485

42. Kashork CD, Sutton VR, Fonda Allen JS, Schmidt DE, Likhite ML, Potocki L, et al. Low or absent unconjugated estriol in pregnancy: an indicator for steroid sulfatase deficiency detectable by fluorescence in situ hybridization and biochemical analysis. Prenat Diagn 2002;22:1028-32. 43. Ballabio A, Ranier JE, Chamberlain JS, Zollo M, Caskey CT. Screening for steroid sulfatase (STS) gene deletions by multiplex DNA amplification. Hum Genet 1990;84:571-3. 44. Basler E, Grompe M, Parenti G, Yates J, Ballabio A. Identification of point mutations in the steroid sulfatase gene of three patients with X-linked ichthyosis. Am J Hum Genet 1992;50:438-91. 45. Morita E, Katoh O, Shinoda S, Hiragun T, Tanaka T, Kameyoshi Y, et al. A novel point mutation in the steroid sulfatase gene in X-linked ichthyosis. J Invest Dermatol 1997;109:244-5. 46. Alperin ES, Shapiro LJ. Characterization of point mutations in patients with X-linked ichthyosis: effects on the structure and function of the steroid sulfatase protein. J Biol Chem 1997;272: 20756-63. 47. Oji V, Traupe H. Ichthyoses: differential diagnosis and molecular genetics. Eur J Dermatol 2006;16:349-59. 48. Schwartz RA, Williams ML. Acquired ichthyosis: a marker for internal disease. Am Fam Physician 1984;29:181-4. 49. Shwayder T. Ichthyosis in a nutshell. Pediatr Rev 1999;20: 5-12. nemo A, Sjo den PO, Johansson E, Vahlquist A, Lindberg M. 50. Ga Health-related quality of life among patients with ichthyosis. Eur J Dermatol 2004;14:61-6. 51. Phipps A. Disorders of cornification: the multiplex presentation of ichthyosis. J Am Osteopath Coll Dermatol 2004;1: 8-12. 52. Goldsmith LA, Baden HP. Propylene glycol with occlusion for treatment of ichthyosis. JAMA 1972;220:579-80.

53. Lykkesfeldt G, Hyer H. Topical cholesterol treatment of recessive X-linked ichthyosis. Lancet 1983;2:1337-8. 54. Williams ML, Elias PM. Enlightened therapy of the disorders of cornification. Clin Dermatol 2003;21:269-73. 55. Siegfried EC. Neonatal skin and skin care. Dermatol Clin 1998; 16:437-46. 56. Thomas JR, Doyle JA. The therapeutic uses of topical vitamin A acid. J Am Acad Dermatol 1981;4:505-13. 57. Haas AA, Arndt KA. Selected therapeutic applications of topical tretinoin. J Am Acad Dermatol 1986;15:870-7. 58. Frost P, Weinstein GD. Topical administration of vitamin A acid for ichthyosiform dermatoses and psoriasis. JAMA 1969;207: 1863-8. 59. Muller SA, Belcher RW, Esterly NB, Lochner JC, Miller JS, Roenigk H Jr, Weissman L. Keratinizing dermatoses: combined data from four centers on short-term topical treatment with tretinoin. Arch Dermatol 1977;113:1052-4. 60. Hofmann B, Stege H, Ruzicka T, Lehmann P. Effect of topical tazarotene in the treatment of congenital ichthyoses. Br J Dermatol 1999;141:642-6. AB, Buka RL. 61. Nguyen V, Cunningham BB, Eichenfield LF, Alio Treatment of ichthyosiform diseases with topically applied tazarotene: risk of systemic absorption. J Am Acad Dermatol 2007;57(Suppl):S123-5. 62. Freiberg RA, Choate KA, Deng H, Alperin ES, Shapiro LJ, Khavari PA. A model of corrective gene transfer in X-linked ichthyosis. Hum Mol Genet 1997;6:927-33. 63. Jensen TG, Jensen UB, Jensen PK, Ibsen HH, Brandrup F, Ballabio A, et al. Correction of steroid sulfatase deficiency by gene transfer into basal cells of tissue-cultured epidermis from patients with recessive X-linked ichthyosis. Exp Cell Res 1993; 209:392-7.