INVITED ARTICLE

Complications of ichthyosisbeyond the skin

Lucia Z. Diaz*, John C. Browning†, Aimee C. Smidt§,William B. Rizzo¶ & Moise L. Levy‡*Department of Dermatology, University of Texas Health ScienceCenter-Houston, Houston, †Department of Pediatrics and Division ofDermatology, University of Texas Health Science Center at San Antonio, SanAntonio, ‡Pediatric Dermatology, Dell Children’s Medical Center, Austin,Texas, §Departments of Dermatology and Pediatrics, University of NewMexico School of Medicine, Albuquerque, New Mexico and ¶Department ofPediatrics, University of Nebraska Medical Center, Omaha, Nebraska

ABSTRACT: Although ichthyoses are noted for their skin features, like many dermatologic conditions,patients are often impacted in ways beyond the skin. Much has been described in recent years regardingquality of life and skin disorders. This is certainly the case for ichthyosis. For neonates or others withdiffuse involvement of their skin, nutritional needs are often exceeding normal requirements. These canoften result in growth abnormalities. Lastly, with specific subtypes of ichthyosis, compromise of tissuesaround the eyes and ears can be of concern to some patients. Certainly, some forms of ichthyosis areroutinely complicated by such findings. It is important for practitioners caring for individuals withichthyosis to have these issues in mind.

KEYWORDS: ichthyosis, quality of life, growth, eye and ear

Introduction

This section will deal with issues of great impor-tance to patients and families dealing with ichthyo-sis. First of all, the impact of this condition on theoverall quality of life will be addressed by Dr Smidt.This is a complex set of concerns that vary inintensity for individuals dealing with ichthyosis.Nutrition and growth are of great importance forall patients with diffuse skin disorders. This is noexception for ichthyosis and has been reviewed byDrs Diaz, Browning, and Levy. Lastly, various clini-

cal types of ichthyosis are complicated by difficul-ties involving the eyes and ears; several suchproblems will be reviewed by Dr Rizzo.

Ichthyosis quality of life

The spectrum of ichthyoses can be quite disfigur-ing, depending on type, severity and extent of bodysurface area. The head/neck/ears and extremitiesare typically involved, which are highly visible toothers and may negatively impact the patient’sself-image and/or quality of life (QoL) in variousways. As one affected individual verbalized: “Myappearance is scary, ugly, or looking like a creepymonster. Sometimes it’s hard looking at myself inthe mirror.” (1) Because ichthyoses are relativelyrare, the general public is not usually familiar with

Address correspondence and reprint requests to: Moise L.Levy, MD, Pediatric Dermatology, Dell Children’s MedicalCenter, 4900 Mueller Blvd., Austin, Texas 78723; or email:mlevy@sfcaustin.com.

39

Dermatologic Therapy, Vol. 26, 2013, 39–45Printed in the United States · All rights reserved

© 2013 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPYISSN 1396-0296

these conditions. Acceptance among peer groupsand lay population may be difficult and interper-sonal relationships are often adversely affected.Significant physical symptoms are also caused bythese disorders, namely skin discomfort, xerosis,pruritus, hypo- or anhidrosis/heat intolerance,vision loss/ophthalmologic abnormalities, andpotential joint limitations, which can alter an indi-vidual’s ability to perform and/or enjoy dailyactivities.

As noted previously, natural history varies andalso has impact on QoL: for example, ichthyosisvulgaris (IV) may increase in scale-up untilpuberty, at which point it may begin to decrease inintensity as the patient ages. Lamellar ichthyosis(LI), congenital ichthyosiform erythroderma (CIE),and bullous variants are usually defined atbirth/early childhood and may be stable or worsenthrough young childhood to puberty and adult-hood. X-linked recessive ichthyosis (XLI) often per-sists into adulthood with little change in the initialpresentation but is usually milder overall. As thereis presently no cure, treatment is often symptom-atic, labor-intensive, and time-consuming, andincludes prolonged bathing, use of various topicalemollients, keratolytics and medications, andsometimes systemic retinoids.

Treatment itself can have a negative impact onQoL, and further, many of the above modalities arenot “prescribed” and therefore not reimbursed bytypical insurance coverage, which translates intosignificant time and expense for the affected indi-vidual. One study specifically examining the finan-cial burden of the congenital ichthyoses found thatthe annual average mean cost to a patient was$3192 (societal/payer) and $1182 (personal/out-of-pocket) (2). Of note, over-the-counter remediescomprised 80% of personal medications and justover 50% of the total mean cost incurred. Asthis group notes, insurance carriers usually do notreimburse for these modalities, leaving low-income patients at high risk for suboptimal treat-ment and perhaps overutilization of prescriptionmedications because of lack of access and poorlycontrolled skin disease.

Recently, there has been increased recogni-tion of QoL issues in many dermatologic condi-tions, including the ichthyoses. A small subsetof adults surveyed with the Nottingham HealthProfile (NHP) and interviewed in focused sessionsreported that ichthyosis had negatively affectedtheir life and that childhood was the period ofgreatest affliction (3). Common themes amongthose childhood recollections included shyness,discrimination/bullying, feeling like an “outsider,”

“I have had a tough life” and “I have always beenunhappy.” Physical symptoms were also noted tolimit activities during childhood, such as participa-tion in sports because of heat intolerance. Ichthyo-sis was noted to affect clothing choice, peer–peerinteractions, romantic/sexual relationships, andchoice of profession.

There have been few other published reportsspecifically quantifying impact of ichthyoses onQoL. Studies typically utilize the Dermatology LifeQuality Index (DLQI) to measure QoL of older ado-lescent (age 17+) and adult patients. Some groupshave also employed general health-related QoLindices such as the Health Related QoL, NHP, andShort Form-36.

Results show that ichthyosis affects QoL similarto, or more so than, other chronic skin diseaseslike atopic dermatitis and psoriasis (4). The nega-tive impact is more substantial in patients with LI> IV > XRI, and more significant in adults versuschildren overall. Females generally report greaterQoL impairment, specifically in subscales of dailyactivities and treatment than males (5). The degreeof both erythema and hyperkeratosis, measuredaccording to the validated Congenital Ichth-yoses Severity Index, are associated with higher(worse) QoL scores. These factors also resultedin increased resource utilization/practitionervisits (6).

There have been no specific studies of theimpact of ichthyosis on QoL in affected children.One subgroup of pediatric patients within a largerreview utilized the Children’s CDLQI included 15children (ages 5–16 years) with various ichthy-oses.(3) In this group, parents expressed the mostconcern over their children’s symptoms andtreatment.

Groups such as the Foundation for Ich-thyosis and Related Skin Types (http://www.firstskinfoundation.org) and the Ichthyosis SupportGroup (http://www.ichthyosis.org.uk) are instru-mental in providing support, information, anda sense of community for such patients andtheir caregivers. Efforts to provide education andexposure to similar patients may also decrease phy-sician visits and/or time and money spent dailyon symptomatic treatments. Clinical and geneticcounseling also play very important roles inproviding multidimensional patient care. Thus,it is vital for the practitioner to recognize the impactof these disorders on QoL, beyond what might bereported as physical signs and symptoms, and toinclude QoL assessment in evaluations and treat-ment plans for patients with the congenitalichthyoses.

Diaz et al.

40

Growth failure and vitaminD-deficient rickets in ichthyosis

Hereditary and acquired ichthyoses are disordersof cornification characterized by defective desqua-mation with hyperkeratosis with or without scaling(7). Abnormal protease activity, lipid metabolicdefects, epidermal structural protein mutations,and defective cellular communication lead to anepidermal barrier dysfunction (8). In addition tomanaging the skin, these children should be moni-tored for growth failure and vitamin D-deficientrickets.

Vitamin D-deficient rickets and hyperparathy-roidism have been described in cases of epider-molytic ichthyosis, IV, LI, XLI and nonbullous CIE(9–13). Although most cases of ichthyosis withrickets have been reported in developing countries,nutritional deficiencies in developing countries donot completely explain why rickets is seen in thesecases.

Milstone et al. (14) reported elevated parathy-roid hormone and low-to-normal 25-hydroxyvitamin D levels in children with various keratiniz-ing disorders. They postulated that this resultsfrom either the defective synthesis of vitamin D orexcess loss of calcium through an injured epider-mis. More recently, a cross-sectional study in Indiathat included 45 children with disorders of cornifi-cation showed that having ichthyosis or anotherkeratinizing disorder increases the risk of vitaminD deficiency and rickets several-fold. (9) Theyconcluded that vitamin D deficiency is seen inrickets because of decreased sun exposure fromintolerance or embarrassment and defective skinunable to synthesize vitamin D, especially in darkindividuals.

Moreover, after evaluating gastrointestinalstructure and function and nutritional status in 10American children with ichthyosis and growthfailure, Fowler et al. (15) concluded that nutritionaldeficiencies and gastrointestinal dysfunction arenot primary reasons for growth failure. The chil-dren’s calorie count was adequate to supportnormal growth and there were no significant nutri-tional deficiencies except for low 25-hydroxyvitamin D in 3 of 10 patients. They concluded thatchildren with ichthyosis have an increased caloricneed because of an impaired skin barrier. As aresult, an early nutritional assessment and caloricsupplementation is essential to maximize growth.Children with ichthyosis also lose water easilythrough their skin. This leads to dehydration andconstipation, which can interfere with further foodintake. Therefore, children with ichthyosis should

be given extra fluids and stool softeners whenneeded.

Calcium and intramuscular or oral vitamin Dhave been shown to improve rickets but not ich-thyosis. (10,11) This is supported by a previous trialwhere oral 1-alpha-hydroxy vitamin D3 was noteffective in treating ichthyosis (16). Topical calcipo-triene (a vitamin D analog), however, reduces thescaling and roughness of treated ichthyotic skinwithout significant systemic absorption. (10, 17) Itis considered a safe medication and was not foundto cause hypercalcemia in adults with LI who usedup to 120 g weekly (17).

It is important to try to prevent rickets, vitaminD insufficiency, and growth failure in patientswith ichthyosis. Assessment of growth parametersand imaging should be done in these children.Housz-Oro et al. (18) recommend serial bonemineral density studies in addition to checkingserum 25-hydroxy vitamin D levels in patientswith ichthyosis. Vitamin D insufficiency is definedas serum 25-hydroxy vitamin D of <20 ng/mLwhile insufficiency is defined as <21–29 ng/mL(19). Experts recommend a level of at least 30 ng/mL. (19) Chouhan et al. (9) suggests treating ich-thyosis patients with prophylactic lifelong vitaminD and a vitamin D-enriched diet. A high-calorie diet and fluid supplementation is alsoessential.(15)

More studies are needed to determine if growthfailure and vitamin D-deficient rickets result froman innate pathological process in ichthyosis oras a consequence from the impaired epidermalbarrier with hyperkeratosis. The impact of acitretinon growth and bone mineralization in ichthyosisneeds to be studied. A multicenter study includingpatients with various skin types and environmentswould further elucidate the causes and impli-cations of growth failure and rickets seen inichthyosis.

Ocular abnormalities associatedwith ichthyosis

A variety of ocular abnormalities are asso-ciated with ichthyosis and ichthyotic syndromes(Table 1). The most commonly seen abnormalitiesinclude ectropion, corneal alterations, cataracts,and retinal defects. Some of these can lead to visualimpairment and even blindness if not treated in atimely fashion. An ophthalmologic evaluation isindicated for many, if not most, patients with ich-thyosis to help in diagnosis and management.

Non-cutaneous complications of ichthyosis

41

Tab

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Ocu

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abn

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Typ

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acts

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lar

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ion

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tic

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pla

sia

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rnea

ld

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tsC

olo

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ma

Nys

tagm

us

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oto

ph

ob

ia

Har

leq

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ich

thyo

sis

✓✓

✓

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ella

ric

hth

yosi

s✓

✓

X-l

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d(s

tero

idsu

lfat

ase

defi

cien

cy)

✓

Au

toso

mal

rece

ssiv

eco

nge

nit

alic

hth

yosi

s(c

on

gen

ital

ich

thyo

sifo

rmer

yth

rod

erm

a)

✓�

✓

Ker

atit

is-i

chth

yosi

s-d

eafn

ess

syn

dro

me

✓✓

✓✓

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oid

sulf

atas

eco

nti

guo

us

gen

ed

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ion

✓✓

Sjö

gren

–Lar

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nsy

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✓✓

✓✓

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✓

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ency

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ency

✓✓

✓✓

✓

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dys

pla

sia

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X-l

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✓✓

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ELO

VL4

defi

cien

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✓

Mu

ltip

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defi

cien

cy✓

✓

Neu

tral

lipid

sto

rage

dis

ease

wit

hic

hth

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s✓

Ref

sum

dis

ease

✓✓

✓

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-dys

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✓

Feat

ure

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ce:✓

✓✓

,typ

ical

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nt;

✓✓

,fre

qu

ent

(>50

%);

✓,o

ften

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%);

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ereb

rald

ysge

nes

is,n

euro

pat

hy,

ich

thyo

sis

and

pal

mo

pla

nta

rke

rato

der

ma;

CH

IME

,ocu

lar

colo

bo

mas

,hea

rtd

efec

t,ic

hth

yosi

form

der

mat

itis

,men

talr

etar

dat

ion

and

ear

ano

mal

ies;

IFA

P,ic

hth

yosi

sfo

llicu

lari

s,al

op

ecia

,an

dp

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top

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bia

;ME

DN

IK,m

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atio

n,e

nte

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per

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reti

nit

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igm

ento

sa.

Diaz et al.

42

Ectropion is a condition caused by verticalshortening of the anterior lamella of the eyelid thatresults in outward eversion of the eyelid. Inpatients with ichthyosis, the hyperkeratosis affect-ing the lids causes shortening and eventual scar-ring of the eyelid (cicatricial ectropion). Ectropionoccurs frequently in more severe forms of ichthyo-sis, such as harlequin ichthyosis and LI, but rarelyin milder diseases (e.g., IV). It can be present atbirth or it may develop more slowly over time. Itcommonly affects the lower eyelids, but can alsoinvolve the upper lids. Failure to drain tearsthrough the tear duct results in epiphora, and theinability to completely close the eyelids causesexposure of the cornea to the atmosphere withconsequent corneal perforation, scarring andblindness. The exposed conjunctiva can thickenand become keratinized as well.

The treatment of ectropion is directed at pro-tecting the cornea from developing exposure kerat-opathy. In infants born with severe ichthyosis,ectropion is an urgent medical problem thatrequires immediate attention (20). Medical therapybegins with lubricating eyedrops consisting of0.5–1% carboxymethylcellulose, or ointment if thelids cannot be completely closed, especially whensleeping. Room humidifiers help maintain a moistenvironment for the eye. Topical therapy of theeyelids with retinoid creams (0.05–1% tazarotene)or 10% N-acetylcysteine emulsion in 5% urea canprevent ectropion from developing, and evenreverse mild cases (21,22). Severe ectropionrequires surgical procedures that involve lengthen-ing of the anterior lamella and/or lateral canthop-lasty with grafting of relatively unaffected skin(23,24). For the best outcome, an experienced oph-thalmic surgeon should do the procedure. Long-term resolution of the ectropion may not becomplete if hyperkeratosis recurs on the eyelid(25). In stubborn cases, systemic retinoids may behelpful.

Corneal defects occur in several forms of ich-thyosis and as a complication of untreated ectro-pion. Patients with keratitis-ichthyosis-deafness(KID) syndrome have a vascularizing keratitis thatbegins in childhood or early adolescence andadvances progressively in some patients to blind-ness (26). Neovascularization and conjunctivaliza-tion of the corneal surface and stroma results inscarring. The severity of the keratitis in KID syn-drome, however, varies widely and the therapeuticapproaches are accordingly broad. Treatment ofthe ichthyosis with systemic retinoids offers nobenefit for the eye. Due to the progressive natureof the keratitis, some severely affected patients

require surgical keratectomy with transplantationof limbal tissue and amniotic membrane (27).Corneal transplantation is usually ineffective.

XLI (steroid sulfatase deficiency) is associatedwith corneal opacities in approximately 24% ofpatients (28). The opacities usually develop in thedeep posterior corneal stroma close to Descemet’smembrane, but can rarely involve the more ante-rior stromal layer. The opacities are small andvision is not affected.

Corneal scarring and erosions with corneal vas-cularization can also be seen in ichthyosis follicu-laris, alopecia, and photophobia (IFAP) syndrome(29). Acitretin therapy may result in a modestimprovement in corneal erosions. In patients withichthyosis originating from multiple sulfatase defi-ciency, clouding of the corneas may be associatedwith other systemic features of hepatosplenom-egaly, coarse facies, and central nervous systemdemyelination.

Retinal abnormalities are characteristic ofseveral ichthyoses. Most patients with Sjögren–Larsson syndrome, an inborn error of fatty alde-hyde metabolism, have a distinctive crystallinemaculopathy with the appearance of so-called glis-tening white dots surrounding the fovea. Themacula may degenerate and it has a unique defi-ciency of macular pigments (30). In the context ofichthyosis and neurologic symptoms, the macul-opathy is a reliable diagnostic sign. Patients withcerebral dysgenesis, neuropathy, ichthyosis andpalmoplantar keratoderma (CEDNIK) syndromehave macular atrophy along with the other sys-temic findings. No effective therapy is available forthe retinal defects in these diseases.

Retinitis pigmentosa (RP) develops in patientswith Refsum disease, an autosomal recessive disor-der with ataxia, deafness, peripheral neuropathy,cardiac conduction defects, and ichthyosis. Nightblindness is an early symptom that precedes theappearance of ichthyosis and neurologic disease.RP also has also been reported in some patientswith contiguous gene deletions involving the Xchromosome and steroid sulfatase gene, a raregenetic cause for XLI associated with neurologicsymptoms.

Therapy of RP is problematic. The symptoms ofRefsum disease are caused by accumulation ofphytanic acid owing to it defective oxidation. Phy-tanic acid is an unusual branched-chain fatty acidthat is derived from the diet (e.g., green vegetablesand dairy products). Some of the patients’ symp-toms, including the ichthyosis and ataxia, respondto dietary restriction of phytanic acid together withplasmapheresis that lowers toxic phytanic acid

Non-cutaneous complications of ichthyosis

43

stores. However, the RP, once established, does notregress.

Optic neuropathy is noted in at least two syn-dromic forms of ichthyosis: CEDNIK syndromeand deficiency of steroid 5a-reductase type-3,which is associated with defective protein glycosy-lation. No effective treatment is known.

Photophobia is a common symptom in IFAP syn-drome, Sjögren–Larsson syndrome, trichothio-dystrophy with ichthyosis (Tay syndrome), and therecently described ELOVL4 enzyme deficiency(Table 1). Although no specific therapy is effectivein these diseases, the use of sunglasses helps mostpatients when they are outside on bright days.

Cataracts occur in several of the ichthyosis,including neutral lipid storage disease with ich-thyosis (NLSDI), CEDNIK syndrome, and mentalretardation, enteropathy, deafness, peripheralneuropathy, ichthyosis, keratoderma (MEDNIK)syndrome and Conradi-Hunermann-Happle syn-drome (X-linked dominant form of chondrodyspla-sia punctata). Therapy of the visual impairment insome of these ichthyotic disorders may benefit fromcataract surgery, although experience is limited.

Nystgmus is prominent in those forms of syn-dromic ichthyosis that have brain malformationsand early visual impairment (Table 1). No effectivetherapy exists.

Colobomas of the eye are characteristic of twosyndromes with ichthyosis. Ocular colobomas,heart defect, ichthyosiform dermatitis, mentalretardation and ear anomalies (CHIME) syndromeis a rare ichthyotic disorder with retinal and chor-oidal colobomas along with other non-oculardefects (31). Colobomas of the iris and/or choroid-retina are ocular developmental defects in patientswith the ichthyotic syndrome caused by steroid5a-reductase type-3 deficiency. Visual impairment,nystagmus, and less commonly cataract, micro-phthalmia, glaucoma, and optic nerve hypoplasiaalso occur. This disease has only recently beendescribed and no specific therapy has beenreported for the ocular defects.

Ear abnormalities associatedwith ichthyosis

A practical issue for many patients with one of themore severe forms of ichthyosis is the developmentof diminished hearing because of scale build-upand blockage of the external auditory canal. Thisproblem requires regular curettage and debride-ment of the excess scale by a physician to maintainhearing. In LI, harlequin ichthyosis and other

severe forms of ichthyosis, systemic retinoids willimprove the hyperkeratosis throughout the body,including the external auditory canal. Neverthe-less, these drugs are not primarily used for treatingthe hearing impairment caused by scale build-upalone.

Sensorineural deafness is a feature of severalsyndromic forms of ichthyosis. In KID syndrome,moderate-to-profound sensorineural deafness is acharacteristic finding that defines the disease.Deafness is also present in many patients withCEDNIK syndrome, MEDNIK syndrome, NLSDI,and Refsum disease.

The deafness in these ichthyotic disorders isusually helped with the use of hearing aids.Cochlear implants have proved beneficial for thedeafness in KID syndrome (32) and may be usefulfor other disorders. For patients with Refsumdisease, aggressive dietary phytanic acid restrictionmay prevent progressive loss of hearing if startedearly in the disease.

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