x-linked ichthyosis an oculocutaneous

7/28/2019 X-Linked Ichthyosis an Oculocutaneous

1/6

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 possibleextracutaneous manifestations. It was first described as a distinct type of ichthyosis in 1965. XLI is caused bya deficiency in steroid sulfatase activity, which results in abnormal desquamation and a retentionhyperkeratosis. XLI is usually evident during the first few weeks of life as polygonal, loosely adherenttranslucent scales in a generalized distribution that desquamate widely. These are quickly replaced bylarge, dark brown, tightly adherent scales occurring primarily symmetrically on the extensor surfaces andthe 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 usuallymade clinically, as the histopathology is nonspecific, but confirmation may be obtained through eitherbiochemical or genetic analysis. Treatment should focus on cutaneous hydration, lubrication, andkeratolysis and includes topical moisturizers and topical retinoids ( J Am Acad Dermatol 2010;62:480-5.)

Key words: genodermatosis; hyperkeratosis; ichthyosis; X-linked.

The term ichthyosis refers to a group ofhereditary and acquired cutaneous disordersof keratinization. Ichthyosis is derived from

the Greek root ichthys, which means fish inEnglish.1 Ichthyosis is appropriately named, giventhat the skin of affected patients often resembles fishscales. This category ofdiseases was first described in1808 by Robert Wilan,2 a physician to the LondonDispensary.3 Ichthyosis was further studied andexpanded to include a number of distinct diseasessuch as ichthyosis vulgaris, X-linked ichthyosis (XLI),lamellar ichthyosis, and epidermolytic hyperkerato-sis. XLI specifically was first recognized by Wells andKerr4 in 1965.

EPIDEMIOLOGY AND ORIGINXLI is a hereditary disorder of cutaneous keratin-

ization, with possible extracutaneous manifestations,inherited in an X-linked recessive fashion. It is the

second most common type of ichthyosis, with aprevalence of 1 in 6000, affecting almost exclusively

males.5 XLI has rarely been described in homozy-gous women who were offspring of an affected manand a female carrier.6,7 There is no noticeable racialor geographic predilection.8

XLI is most commonly caused by a genetic defectleading to a deficiency of the enzyme steroid sulfa-tase (STS), also known as arylsulfatase C.9-11A smallnumber of cases may be the consequence of othergenetic alterations ofthe X chromosome not directlylinked to the Stsgene.12 The gene coding for STS hasbeen mapped to the short arm of the X chromosomeat Xp22.3.13,14 This region of the X chromosomeescapes normal inactivation, so female carriers can-not develop XLI through functional mosaicism.15

Approximately 80% to 90% of cases of XLI are a resultof complete deletions of the 146-kilobase gene.16

STS catalyzes the hydrolysis of aryl and alkyl steroidsulfates such as dehydroepiandrosterone sulfate,cholesterol sulfate, pregnenolone sulfate, and an-

drostenediol-3-sulfate to produce biologically activesteroids.16,17 Beyond the skin, STS has a wide varietyof physiologic functions in the breast, immune sys-tem, brain, reproductive tract, osteoblasts, leuko-cytes, and thrombocytes.16

PATHOPHYSIOLOGYSTS is normally found within the epidermis and is

thought to play a role in active cutaneous steroidproduction and lipid regulation.16 Lipids normallymake up 11% of the epidermis; 10% of these lipids

are sterols such as cholesterol sulfate, which is the

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: [email protected].

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

480
mailto:[email protected]:[email protected]


2/6

substrate for STS.8,18 Physiologic breakdown ofcholesterol sulfate leads to corneodesmosome deg-radation and normal desquamation.19 A deficiencyof STS results in the accumulation of cholesterolsulfate in the membranes of stratum corneum cells.20

Cholesterol sulfate is thought to play a role inmembrane integrity and normal desquamationwithin the stratum corneum.Therefore, a pathological in-crease in quantity of choles-terol sulfate results inincreased intracellular stabil-ity and cohesion.18 The endresult is partial retentionhyperkeratosis with a pheno-type of excess scaling.21

CLINICAL FEATURESThe first manifestation of

XLI may be delayed or pro-longed labor in mothers ofaffected fetuses as a result ofthe absence of STS in the fetalplacenta, leading to de-creased levels of estrogen and insufficient dilationof the cervix.22,23 XLI, however, is not usuallydetected until the first few weeks of life whenpolygonal, loosely adherent translucent scales beginto appear in a generalized distribution and desqua-mate widely.24 They quickly develop into large, dark

brown, tightly adherent scales occurring primarily onthe extensor surfaces and the side of the trunksymmetrically (Figs 1 and 2). These scales are oftennoted by the casual observer to look similar to thescales of a fish and to have a dirty appearance.Initially the skin on the scalp, preauricular surfaces,and neck is almost always affected, but scales in thisdistribution tend to largely disappear throughoutchildhood.8 Consequently lower extremity altera-tions tend to be more prominent in patients afterearly childhood. Flexural surfaces are often affected,whereas the palms, soles, hair, and nails are usually

spared.8

Patients with XLI also have decreasednumbers of sweat glands and, hence, a reductionin sweat production.25

Extracutaneous findings are common in patientswith XLI as well (Table I). Ocular abnormalities areseen frequently in the ichthyoses in general. Theseinclude asymptomatic irregularities of the eyelids,conjunctiva, cornea, lens, and fundus.26 Ocularfindings may occur in isolation or as part ofichthyosis-related syndromes such as keratitis-ich-thyosis-deafness syndrome and ichthyosis-follicula-ris-alopecia-photophobia syndrome.27,28 Corneal

opacities are the most common alteration seen in

XLI, normally appearing during adolescence or earlyadulthood.8 These asymptomatic fine, flourlikeopacities can be seen in between 10% to 50% ofpatients diffusely deposited in the posterior cornealstroma or Descemet membrane.29-31 These cornealopacities may present in 25% of female carriers as,interestingly enough, the only finding related to

XLI.30 Although they almostnever affect visual acuity inand of themselves, they maylead to recurrent cornealerosions.26

Cryptorchidism is anotherextracutaneous finding, oc-curring in approximately20% of those with XLI.32

There is also an increasedrisk of testicular germ cell

cancer with XLI, which isindependent of testicularmaldescent.33,34 It is unclearwhether the increased risk ofcryptorchidism in XLI iscaused by the deficiency of

STS or concurrent mutations in nearby genes of theXchromosome involved in testicular descent.35

However, patients have been shown to have normaltestosterone levels, sexual development, andfertility.11

Neurologic findings may also be found in patients

with XLI, often occurring as manifestations of con-tiguous gene syndromes. These abnormalities in-clude epilepsy with electroencephalographicfindings, mental retardation, and hyposmia.36 Othergeneral alterations have rarely been described inpatients with XLI. These findings include pylorichypertrophy, congenital defect of the abdominalwall, acute lymphoblastic leukemia, bilateral peri-ventricular nodular heterotopia, and end-stage renalfailure.36-39 Contiguous gene involvement in patientswith XLI can result in a variety of syndromes includ-ing Rud syndrome, Conradi syndrome, and

Kallmann syndrome.36

Patients with Rud syndromeexhibit cryptorchidism, retinitis pigmentosa, mentalretardation, and epilepsy.40 Shortening of the limbs,epiphyseal stippling, craniofacial defects, short stat-ure, and chondrodysplasia punctata are all featuresof Conradi syndrome.41 Kallmann syndrome is hy-pogonadotropic hypogonadism with associatedanosmia.

DIAGNOSISThe diagnosis of XLI may be suggested during the

prenatal course after a careful family history. History

of a skin disease with significant scaling present in

CAPSULE SUMMARY

d X-linked ichthyosis is an X-linked

recessive disorder of keratinization

caused by a deficiency in steroid

sulfatase activity.

d Mild scaling in the first few days of life

evolves to prominent brownish,

polygonal, firmly adherent scales.

d Corneal opacities, cryptorchidism, and

other abnormalities may be evident.

d Diagnosis is clinical and is confirmed by

biochemical or genetic analysis.

J AM ACAD DERMATOLVOLUME 62, NUMBER 3

Fernandes, Janniger, and Schwartz 481


3/6

only the male relatives of the mother should arouse

suspicion. If low to absent levels of estriol aredetected during the triple screen for alpha fetopro-tein, human chorionic gonadotropin, and estriolduring the second trimester, this should alert thephysician to the possibility of XLI in the fetus.42

A birth history involving a prolonged or complicatedlabor provides pertinent information as well. Afterbirth, a complete history and physical examinationaids largely in the identification of XLI. The timecourse of the presentation is important, remember-ing that 3 of 4 patients experience scaling by 1 weekof life.21 Drawing the family pedigree may elucidate

the mode of inheritance. Special attention should be

paid to the distribution, quality, and quantity of anyscaling.22 An eye examination demonstratingcomma-shaped opacities of the posterior capsulecan also be quite useful in terms of supporting thecorrect diagnosis.22

The diagnosis of XLI may be confirmed throughbiochemical or genetic analysis. Prenatal identifica-tion can be made by detecting decreased estrogen

levels and the presence of nonhydrolyzed sulfatedsteroids in maternal urine.38 If the genetic defect ofthe Sts gene in the family is known, Southern blot,fluorescent in situ hybridization, or polymerasechain reaction can be performed on chorionic villior amniotic fluid samples.43 The diagnosis of XLI isusually confirmed biochemically or genetically afterbirth, however. Serum protein electrophoresis maybe performed to show increased mobility of the beta-lipoprotein fraction as a result of elevated serumcholesterol sulfate levels.21 Direct biochemical tech-niques can be used to demonstrate deficiency of STSactivityin skin fibroblasts, leukocytes, and keratino-cytes.8 Southern blot, fluorescent in situ hybridiza-tion, and polymerase chain reaction are currentmethods for confirming a causative mutation forXLI. Sts gene deletions can be identified throughthese techniques, but the few cases caused bypointmutations instead of deletions can be missed.44-46

Skin biopsy for histopathology is generally notuseful in confirming a diagnosis of XLI becausemicroscopic changes are often subtle and nonspe-cific. Affected skin may appear normal or resembleskin affected by ichthyosis vulgaris.21 One seeshyperkeratosis with varying degrees of hypergranu-

losis in the epidermis (Fig 3).22 The dermis usuallyexhibits edema with mildperivascular inflammation.8

However, a biopsy specimen may be beneficial inconsidering other conditions with specific histopath-ologic features in the differential diagnosis of XLI.

DIFFERENTIAL DIAGNOSISXLI may require distinction from atopic derma-

titis and other ichthyoses, most notably ichthyosisvulgaris and lamellar ichthyosis. Ichthyosis vulgarisis the most difficult to differentiate from XLI, and

can be hereditary or acquired.

47

Ichthyosis vulgaris

Fig 1. Patient with X-linked ichthyosis with characteristiclarge, dark brown, tightly adherent scales across his entireback.

Fig 2. Patient with X-linked ichthyosis with characteristiclarge, dark brown, tightly adherent scales along extensorsurfaces of his upper extremities.

Table I. Extracutaneous manifestations of X-linkedichthyosis

Ocular Corneal opacities (10%-50%)

Genitourinary Cryptorchidism (20%),

germ cell testicular cancer

Orthopedic Chondrodysplasia punctataNeurologic Mental retardation, epilepsy

J AM ACAD DERMATOLMARCH 2010

482 Fernandes, Janniger, and Schwartz


4/6

is associated with follicular keratosis and symmet-ric, light gray scaling that appears after 3 months oflife.1 Flexural surfaces are usually spared, as op-posed to XLI, in which flexural surfaces are oftenaffected.8 The histopathology of ichthyosis vulgarismay appear similar to that of XLI. Biopsy specimengenerally shows basket-weave hyperkeratosis in thestratum corneum, patchy parakeratosis, a markedlydecreased granular cell layer, and perivascularlymphohistiocytic infiltration of the dermis.1

Hereditary ichthyosis vulgaris can be differentiatedfrom XLI because it is inherited in an autosomal-dominant manner. Acquired ichthyosis, on theother hand, is found almost exclusively in adultsand is considered a marker for cancer, infection, orother serious systemic illnesses.48 Despite clinicalsimilarities between the two, XLI can ultimately bedifferentiated from ichthyosis vulgaris, and othercutaneous diseases, by demonstrating a deficiencyof STS.

MANAGEMENT

XLI is an incurable lifelong condition that rarelyaffects normal life functions.49 Most patients with XLIhave disease limited to the skin. The majority of casesimprove with age and do not require treatment.8

Cutaneous symptoms are naturally alleviated duringsummer months as well. However, some patientswith XLI and other types of ichthyoses experience asignificantly reduced quality of life. A 2004 Swedishstudy showed that patients with XLI have a lowerhealth-related quality of life as evidenced by theirresponses to the Dermatology Life Quality Index andStandard Form 36 questionnaires.50 Therefore, life-

style modifications and pharmacologic therapies

should be prescribed when indicated to modulatethe abnormal keratinization by aiding in the shed-ding of excess scale and blocking excessivekeratinization.8

Once the disease is recognized, one should initi-ate topical therapy: cutaneous hydration, lubrication,and keratolysis.22 One option for treatment of XLI isto wear a plastic pajama suit overnight after applying40% to 60% propylene glycol in water to the entirebody every night until excess scales are eliminated.51

Therapy then can be gradually weaned until once-a-week use of the suit maintains clear skin.51 If thepatient is unable to tolerate this therapy, othermeasures can be taken to focus on hydration.Humidifying the home, school, and other environ-ments during cold winter months often proves ben-eficial.22 Bathing etiquette is important as well.Soaking for prolonged periods and mechanical de-

bridement with a roughly textured sponge should beencouraged, and lubricating bath oils followed byapplication 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%, andurea in concentrations of 5% to 10% may be used.22

Goldsmith and Baden52 reported uniformly excellentresults after treating 10 patients with XLI with propy-lene 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 XLItreated and demonstrated that it was superior to ureacream in most cases. Combination therapy with analpha-hydroxy acid and cholesterol cream may be anexcellent option.54 In neonates and infants, however,topical keratolytics should be used with considerablecaution because their immature skin barrier functionand increased body surface area to weight ratio maylead to increased percutaneous absorption and sys-temic toxicity.55

Retinoic acid derivatives such as topical isotreti-noin have also been shown to have considerable

success in treating patients with XLI.56,57

Frost andWeinstein,58 in an early study, demonstrated a betterresponse in 6 of 8 patients with XLI treated withvitamin-A acid versus placebo. A short-term pairedcomparison on two patients with XLI suggested 0.1%tretinoin cream was superior to 0.1% topical tretinoincream.59 Hofmann et al60 recently demonstratedsuperior efficacy of the receptor-selective retinoidtazarotene at 0.05% concentration in the treatment of4 patients with XLI. Systemic absorption of this agentwhen used topically for ichthyoses has since beenshown to be minimal.61 Although it has not been

effectively implemented as of yet, research is

Fig 3. Histopathological picture of X-linked ichthyosisexhibiting subtle hyperkeratosis and hypergranulosis withmild dermal perivascular inflammation (Hematoxylin-

eosin stain; original magnification: 3100.)




5/6

underway regarding the possibility of using genetransfer to treat XLI.62,63

Collaboration with other specialists may be help-ful in successfully treating patients with XLI. Patientsand their families should be referred for geneticcounseling to receive further education regardingXLI and its inheritance pattern. Potential risk in futurepregnancies should be emphasized as well, and theobstetrician should be involved in this aspect ofmanagement. In addition, patients should be advisedto perform regular testicular self-examinations, giventhe increased risk of testicular germ cell cancer inXLI. Physicians should also consider includingtesticular evaluation as part of the physical exami-nation 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.

6. Mevorah B, Frenk E, Muller CR, Ropers HH. X-linked recessive

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 thecausalmechanism. Br J Dermatol2005;152:191-3.8. Hernandez-Martn A, Gonzalez-Sarmiento R, De Unamuno P.

X-linked ichthyosis: an update. Br J Dermatol 1999;141:617-27.

9. Marinkovic-Ilsen A, Koppe JG, Jobsis AC, de Groot WP. Enzy-

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, genet-

ical, 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,

Muller CR, et al. Assignment by deletion mapping of the

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 man-

agement. Am J Clin Dermatol 2004;5:17-29.

22. DiGiovanna JJ, Robinson-Bostom L. Ichthyosis: etiology, diag-

nosis, 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.

28. Traboulsi E, Waked N, Megarbane H, Megarbane A. Ocular

findings in ichthyosis follicularis-alopecia-photophobia (IFAP)

syndrome. Ophthalmic Genet 2004;25:153-6.

29. Haritoglou C, Ugele B, Kenyon KR, Kampik A. Corneal mani-

festations 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 ofpatients 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 testic-

ular 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 cryp-

torchidism 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. Hospital-

stidende 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 DERMATOLMARCH 2010

484 Fernandes, Janniger, and Schwartz


6/6

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 biochem-

ical 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 mul-

tiplex DNA amplification. Hum Genet 1990;84:571-3.

44. Basler E, Grompe M, ParentiG, Yates J, BallabioA. Identificationof

point mutations in the steroid sulfatase gene of three patients

with X-linked ichthyosis. Am J Hum Genet 1992;50:438-91.

45. MoritaE, Katoh O, Shinoda S, Hiragun T, TanakaT, 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 molec-

ular 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.

50. Ganemo A, Sjoden PO, Johansson E, Vahlquist A, Lindberg M.

Health-related quality of life among patients with ichthyosis.

Eur J Dermatol 2004;14:61-6.

51. Phipps A. Disorders of cornification: the multiplex presen-

tation 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.

61. Nguyen V, Cunningham BB, Eichenfield LF, Alio AB, Buka RL.

Treatment of ichthyosiform diseases with topically appliedtazarotene: 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.



x-linked ichthyosis an oculocutaneous

Documents