THE ICHTHYOSIFORM DERMATOSES

(1)

(

Received February 23, 1968; revision accepted for publication May 15, 1968.)

ADDRESS: La Rabida-University of Chicago Institute, East 65th Street at Lake Michigan, Chicago,

Illinois60649.

REVIEW

ARTICLE

THE

ICHTHYOSIFORM

DERMATOSES

Nancy B. Esterly, M.D.

Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland

T

HE TERM ichthyosis describes a group

of heritable disorders which are

char-actenized by cutaneous scaling. The visible scale differentiates these disorders from

xe-roderma in which the skin is dry but does

not visibly desquamate. Many classifica-tions of the ichthyoses have been proposed, but most are descriptive and contribute

lit-tie to an understanding of etiology and pathogenesis. Often clinical variants or

pa-tients with minor associated anomalies have

been categorized separately on an empirical

basis and, in some cases, several names

have been used for one entity to indicate

severity of involvement.

The most useful classification appears to be that of Wells and Kerr,1 who segregated

the various types by their pattern of

inheri-tance and retained the nomenclature in common usage. Differences in clinical

fea-tures and histologic patterns also correlate with these genetically distinguishable types. Thus, with careful attention to the

distribu-tion and type of scale, family history, and skin histology, the physician will be able to classify patients in a meaningful way. Such

an approach is helpful for several reasons. The prognosis, troublesome features, and

degree of handicapping differ for the

var-jous ichthyoses. Sensible genetic counseling,

an important part of

the

management of

such patients, is possible only with the

cor-rect diagnosis. Moreover, clinical investiga-lion of affected individuals will be further confused unless the entity under study is well defined. The need for an

understand-ing of the physiologic and biochemical

de-fects of ichthyotic skin is underscored by the limitations of currently available ther-apy.

The four major types of ichthyosis in-elude: (1) ichthyosis vulgaris, transmitted

as an autosomal dominant trait; (2) sex-linked ichthyosis, transmitted as an X-linked trait; (3) bullous congenital ichthyo-siform erythroderma (CIE

),

inherited as an autosomal dominant trait; and (4)

nonbul-bus congenital ichthyosiform erythro-derma, autosomal recessive mode of inheri-tance

(

Table I). On the basis of available pedigree data, the harlequin fetus is

consid-ered a severe form of the autosomal reces-sive type of CIE. The collodion baby is a

phenotypic expression of several genotypes:

sex-linked ichthyosis and bullous and

non-bullous GTE. A few of the infants with

col-lodion membranes may represent yet

an-other entity, since shedding of the mem-branes has resulted in a completely normal skin. Two types of ichthyosis-ichthyosis

li-neanis circumfiexa and erythrokeratodermia variabilis-have been considered separately

from the foregoing four types because their relationship to the other forms remains un-clear. In addition, a few uncommon syn-dromes may include ichthyosis as a con-stant or variable feature

(

Table II

),

but the clinical and histologic descriptions are insufficient to be certain of the type of

ichthyosis.

Alternative terms used by other authors have been summarized in Table III. A

re-cent study by Frost and Van Scott68 is an

important contribution because, for the first

time, an attempt has been made to group

affected individuals on the basis of a

phys-iologic mechanism, i.e., differences in

eel-lular kinetics

(

see section on pathogenesis). Frost and Van Scott investigated patients with ichthyosis vulgaris, nonbullous CIE

(lamellar ichthyosis

),

and bullous CIE

(2)

IIEVIE\V ARTICLE 991

ICHTHYOSIS

VULGARIS

Ichthyosis vulganis is usually not clini-cally apparent until after the first 3 months

of life and is often milder and more

local-ized than other types of ichthyosis.2’3 The trunk, back more than abdomen, and

exten-son surfaces of the limbs are the sites of

predilection. The flexures are

characteris-tically spared. The forehead and cheeks may be involved in early childhood, bt

scaling in these areas diminishes with age. The scales are fine, white, and branny and

have a “pasted on” appearance. Discrete,

shiny hyperkeratoses on the elbows, knees, and ankles and increased palmar and

plan-tar markings are helpful diagnostic

fea-tures. Keratosis pilanis

(

follicular hyperker-atosis

)

and chapping of the hands and feet

are frequently associated. Many affected

in-dividuals have mamfestations of atopy

(

ec-zema, asthma, or hay fever) or a strong family history of these disorders.I

Biopsy of involved skin

(

Fig. 1

)

shows the following pattern : mild to moderate thicken-ing of the stratum corneum, occasional

plug-ging of the hair follicles with keratotic debris, and patchy areas of corneal cells with

retained nuclei

(

parakeratosis

)

. The

gran-ular layer is usually reduced or absent, but the remainder of the epidermis and the con-figuration of the rete ridges are normal. Ec-crine and sebaceous glands may be reduced

in nuflhl)er. A perivascular infiltrate of

lym-1)hOid cells is sometimes Presetlt in the

uper dermis.4

Ichthyosis vulganis is, as the name

im-plies the most common type of ichthyosis

and is transmitted as an autosomal

domi-nant trait. The incidence in a study of

school children in Berkshire, England, was 1 : 250. Since many children are minimally

affected and improvement with age is

usual, the true incidence may be higher

than is generally appreciated.

SEX-LINKED ICHTHYOSIS

The onset of sex-linked ichthyosis is

al-niost always within the first 3 months of life, but it rearely occurs as late as a year of

a collodion niembrane at birth

(

see section

on collodion baby.

)

Generally, all body

surfaces are affected except for the palms

and soles. Heavy scaling of the scalp, neck,

and side of the face gives the patient an

un-washed appearance that is a dependable

and characteristic finding in childh9od.

In-volvement of one or two flexures, usually

the axillae or antecubital fossae, occurs in

approximately 30sf of these children. In the adult with sex-linked ichthyosis, the abdo-men and lower legs show more prominent scaling and, if there is involvement of the flexural areas, the popliteal rather that the upper extremity fossae are more commonly

affected. In contrast to ichthyosis vulgaris,

the scales are large and dark brown and

may I)e shed )eriOdically

(

“moulting”), most often in the spring and fall. Hyperkera-tosis may be present over the elbows and

knees, but it is not so discrete and shiny as in

ichthyosis vulgaris.

On biopsy

(

Fig. 2 ), the stratum corneum

shows moderate thickening with occasional

parakeratosis, hut plugging of the hair

folli-des is absent. The granular layer is increased

in thickness and the epidermis is

hpertro-phic with prominent rete ridges. Sebaceous

glands are normal in number, but eccninc glands may be decreased. A well

demar-cated chronic inflammatory, perivascular in-filtrate in the upper dermis is a constant feature.4

Fic. 1. Ichthvosis vulgaris. Helpful diagnosis

(3)

4? C 4-C 4,

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.

992 ICHTHYOSIFORM DERMATOSES

0)

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‘I’ABLE II

SYNDROMES INCLUDING ICHTHYOS1S AS A

CONSTANT OR VARIABLE FEATURE

Netherton’s Syndrome

Ichthyosis (nonbullous CIE type) Trichorrhexis invaginata (bamboo hair) Atopic diathesis

Rud’s Syndrome

Mental retardation

Ichthyosis (?nonbullous CIE type) Epilepsy

Infantilism

Sj#{246}gren-Larsson Syndrome

Mental retardation

Ichthyosis (noiibullous CIE type)

Spastic paresis

REVIE\V ARTICLE 993

The prevalence of this type of ichthyosis is unknown. Data are available only for

Berkshire, England, where the incidence was 1 per 6,190 males.6 Prior to the study of Kerr and Wells,6 there were no well defined

clinical and histological criteria for classifi-cation of sex-linked iehthyosis, and affected

individuals were often misdiagnosed.

The disease is transmitted as an X-linked

trait like classical hemophilia and is mani-fested only in males.6 Fifty percent of

fe-male siblings are heterozygous carriers and transmit the condition to their sons. Link-age with the sex-linked blood group Xg

provides additional evidence for transmis-sion on the X chromosome.7’8 Since the het-erozygote cannot be detected clinically and the linkage with Xg is not close, it is not possible to predict which female siblings

will be carriers.

Although the extent and severity of seal-ing tends to increase with age, there are no complications or associated manifestations, and life expectancy is unchanged. A few patients have been described with both

sex-linked ichthyosis and mental deficiency or hypogonadism, but this combination of defects is apparently very rare.3

NONBULLOUS CONGENITAL ICHTHYOSI-FORM ERYTHRODERMA

Nonbullous CIE is usually apparent at birth, although cutaneous changes may not be striking until a few months of age. The harlequin fetus probably represents the most severe degree of this condition; these infants die in utero or shortly after birth.’ Other infants may have a collodion mem-brane and, after shedding of this structure, exhibit the characteristic erythrodenma and hyperkeratosis of CIE.9”#{176} Affected infants are commonly of low birth weight.3

The erythroderma is generalized and in-tense during infancy and childhood but

be-comes less marked with age. The facial skin is red, taut, and shiny with scaling over the

upper face. Greater involvement of the flex-ural areas is characteristic for this form of

Refrum’s Syndrome

Atypical retinitis pigmentosa

Polyneuritis with progressive paresis and cerebellar

signs

Elevated CSF protein

Ichthyosis, deafness, anosmia, pupillary abnormalities, skeletal anomalies, EKG changes (all variable)

ichthyosis, however, individuals with

par-ticularly severe disease may have hyperker-atosis uniformly distributed over the body surface. The scales vary from yellow to

brown-black and, in some eases they form warty excrescences or large, thick, horny plates.

The nails may be stippled and ridged as in psoriasis or they may be greatly thick-ened with subungal accumulations of kera-totic material. Rapid growth of hair and nails has been reported as an inconstant finding. The hair is normal, but there is heavy scaling of the scalp. The palms and

soles are almost always affected, varying in

severity from increased markings to a thick

kenatodenma which may become macerated and malodorous. Ectropion is usual but the eye itself is normal.

(5)

fall, and partial remission may occur in the summer. Individuals with heavy accumula-tion of scales may have difficulty sweating and stiffer heat exhaustion. Extreme prunitus

may also he a troublesome symptom. The histologic pattern

(

Fig. 3

)

resembles that of sex-linked ichthyosis. The epidermis is hyperkeratotic with occasional patchy parakeratosis, increased thickness of the granular layer, papillomatosis. and acantho-sis. A perivascular chronic inflammatory in-filtrate is present in the upper dermis.

Patients with nonbullous CIE usually

have increasing hyperkeratosis with age. Joint mobility can be restricted if the horny plates are thick and extensive. The disease

is inherited as an autosomal recessive trait’ and has been reported in individuals of all races.’’#{176} Consanguinity is common in

fami-lies with this disorder.

BULLOUS CONGEN ITAL ICHTHYOSIFORM

ERYTH RODERMA

Bullous CIE” is also manifested at birth and is extremely variable in severity. Occa-sionally these infants may present as collo-dion babies. In contrast to nonbullous CIE, an association with low birth weight has not been noted.

The hyperkeratosis may be generalized

or localized to the flexures and

peniumbili-Fic. 2. Sex-linked iclithvosis. Note the promiiient granular layer, the hvpertrophic epidermis, and the dermal perivascular, chronic inflammatory infiltrate

(H and E).

cal region; the elbows, knees, wrists, and ankles are also commonly involved. When the face is affected, scaling is usually more prominent oer the lower half. The scales

are hard and shotty and shed in large

quail-tities over short intervals. A l)ackground

er-ythroderma, as in nonbullous CIE, is

char-acteristic. The palms and soles are usually

normal; but, rarely, increased cutaneous markings or gross hyperkeratosis occurs. Hair, eyes, teeth, and nails are normal; ec-tropion is not a feature.

Bullae are the most characteristic

maui-festation and differentiate bullous CIE from other types of ichthyosis. In some patients they may be so severe and generalized

dur-ing the neonatal period as to be life-threat-ening; in others, they are relatively incon-spicuous. Most patients experience

diffi-culty with the blisters in the early years hut

are rarely troubled after the age of 20. The bullae occur in crops. vary in size from 0.5

to several centimeters and, on rupture,

dis-charge clear fluid and leave raw, denuded areas. These lesions initially appear on tile trunk, but in later childhood they often

localize to the lower legs. Secondary

infec-tion with beta-hemolvtic streptococci or

staphylococci is a common problem.

Tile histologic firdings

(

Fig. 4

)

in this type of GTE are diagnostic.’4 There is ex-tensive vacuolation of tile cells in the mid epidermis and granular layer. The bullae are intraepidermal and are first detected in foci of intracellular edema. Many epidermal cells are dyskeratotic and large, clumped

kera-tohyaline granules are prominent in the vacuolated areas . Hvperkeratosis,

papillo-matosis, aiid acanthosis are all characteristic findings, I)ut thes’ var’ in degree. The dermis is normal except for a penivascular infiltrate

of small mononuclear cells.

Bullous CIE is inherited as an autosomal dominant trait.1 Since the bullae, erythema, and hyperkeratosis all decrease with

matu-rity, this disease is most troublesome in the pediatric age group. Ichthyosis hystrix

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REVIEW ARTICLE 995

TABLE III

SYNONYMS FOR THE TYPES OF ICHTHYOSIS

Ichihyosis

Itlithyosis vulgaris

Synonym

Ichthyosis simplex, ichthyosis nitida, ichthyosis nacr#{233}e,pityriasis vulgaris

ex-Jinked iihtlivosis Iehthyosis vulgaris, ichthyosis sauroderma, ichthyosis nigricans, icht hyosis vulgaris serpentina

Nonbullous congenital

iclithyos-iform erythroclerrna an(l/or

Rufous congenital ichtbyosi-form erythroder,na

harlequin fetus

(‘ollodion l)aby

Hyperkeratosis congenita, ichthyosis congenita (larvata, tarda, mitis, inversa),

keratosis rubra congenita, erythrodermie exfoliativa universalis congenita familiaris, generalized ichthyosiform byperkeratosis, ichthyosis bullosa, epi-dermodysplasia hystericoidis bullosa, attenuated ichthyosis fetalis, ichthyosis sebacea, ichthyosis hystrix gravior, lamellar ichthyosis, epidermolytic hyper-keratosis

Ichthyosis congenita, ichthyosis fetalis, keratosis diffuse fetalis, ichthyosis eon-genita gravis, cutis testacea, congenital diffuse malign keratorna, ichthyosis intra-utei ma

Ichthyosis congenita, lamellar exfoliation of the newborn, lamellar iehthyosis,

ichthyosis sebacea ,seborrhea squamosa neonatorum

bizarre patterns

)

is considered a variant of this disorder.”

HARLEQUIN FETUS

Fortunately, harlequin fetus is rare and

the infants are either stillborn or die shortly

after birth. Harlequin fetus is probably the severest form of nonbullous CIE and, there-fore, an autosomal recessive mode of inheni-tance is likely.13 There are several reports

of affected siblingsl68 (none of affected

members in successive generations

)

but a

paucity of cases with consanguinity.

The name probably derives from the

clown-like appearance of the face with the “O”-shaped mouth and from tile tnian-gulan and diamond-shaped hyperkeratotic

plaques on the trunk and limbs resembling

the traditional costume of a harlequin. Tile earliest description of such an infant in tile United States is that of the Reverend Oliver Hart, A.M., of Charlestown, South Carolina.”

On Thursday, April ye 5th, 1750, 1 went to see

a most deplorable object of a child, born the night l)efOre, of one Mary Evans, in Chas’ton. It was

surprising to all who beheld it, and I scarcely

know how to describe it. The skin was dry and

hard, and seemed to be cracked in many places,

somewhat resembling the Scales of a Fish. The

Mouth was large and round, and wide open. It

had no external nose, but two Holes where the

nose would have been. The Eyes appeared to be

lumps of coagulated Blood, turned out, about the

Bigness of a Plumb, ghastly to behold. It had no external Ears, but Holes where the Ears should be. The Hands and Feet appeared to be swoln, were crumpt up, and felt quite hard. The back part of

its Head was much open. It made a strange kind

of noise, very low, which I cannot describe. It lived about eight and forty hours and was alive when I saw it.

Although more detailed reports and au-topsy findings have been published subsequently.2024 Reverend Hart’s observa-tions in 1750 remain a classic description of the disease.

COLLODION BABY

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CIE.’ However, there are patients who have normal skin following the shedding of

the collodion membrane. The name lamel-lar ichthyosis has been used,2527 and the

significance of the membrane is still un-known.

At birth the infant is completely envel-oped in a smooth cellophane-like mem-brane which may, by its tautness, distort the facial features and the digits.283#{176} Less

commonly, there may be only partial

involvement.31 The membrane is shiny and brownish yellow, resembling a coating of eollodion or oiled parchment, and it is usu-ally perforated by both scalp and lanugo hair. It begins to fissure and peel shorfly after birth and often desquamates in large

sheets. An enythema of variable intensity may be present in the underlying skin which, in some cases, may continue to scale or form a new eollodion membrane. Af-feeted infants are frequently premature, but there are no consistent abnormalities of other organ systems.

The collodlion membrane has sometimes been regarded as a physiological variant and attributed to increased cohesion of con-neal cells normally shed in utero and in the first days of life. Bowen32 thought it was a persistent epitrichial layer (periderm) anal-ogous to that retained by certain mammals (e.g., the sloth) until after birth. This

ex-Fic. 3. Nonbullous congenital ichthyosiform erythro-derma: marked thickness of the stratum corneum,

increased granular infiltrate (H and E).

planation is unlikely for several reasons. A new collodion membrane occasionally

forms during the neonatal period, an un-likely event if the material is derived from

a fetal structure. Collodion membranes have never been demonstrated in prema-lure infants of any gestational age. The membrane is perforated by hair, whereas the periderm forms a complete covering over the skin and has disappeared by the time the adnexal structures are completely developed. Finally, there is no consistent retention of nuclei as in the peniderm cells.

The mortality rate for these infants in

contrast to harlequin fetus is low, although the complications of prematurity may

in-crease the risk. The condition of the skin following desquamation is unpredictable; a family history of ichthyosis obviously in-creases the likelihood of persistent disease.

ICHTHYOSIS LINEARIS CIRCUMFLEXA

Ichthyosis linearis circumfiexa is possibly a variant of nonbullous CIE and is eharac-tenized by the triad of migratory senpigi-nous lesions, hyperkeratosis of the flexures, and hyperhidrosis of the palms and soles.’ The paucity of cases makes ge-netic analysis difficult, but inheritance as an autosomal recessive trait seems likely.

Re-ported cases have all been Caucasian with an equal sex distribution.

A diffusely red and scaly skin is noted at birth or during the first year of life. Simul-taneously, on after a period of several weeks, numerous serpiginous lesions with raised erythematous, hypenkeratotic borders appear on the trunk and proximal extremi-ties. The flexural skin becomes

hyperkera-totic and may have a brownish discolor-ation. Unlike nonbullous CIE, palmar and plantar hyperkeratosis is absent. The third finding, hypenhidrosis, has been reported only in affected adults. Hair, teeth, and nails are normal. The histology is consistent with that of nonbullous CIE. Fasting

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REVIEW ARTICLE 997

vitamin A therapy.34 The course is chronic

with occasional, brief, spontaneous remis-sions.

ERYTHROKERATODERMIA VARIABILIS

The lesions of erythrokenatodermia

varia-bilis are of two distinct types :

(

1

)

sharply demarcated, hypenkeratotic plaques with bizarre, irregular outlines; and (2) unre-lated, discrete areas of erythroderma which change in size and location from day to day. This is one of the least common forms of ichthyosis and is probably inherited as an autosomal dominant trait.3638

In 30% of reported eases the manifesta-tions have been noted at birth; in the ma-jority of the remainder, onset was during the first year of life. The erythrodermie le-sions localize to the face, buttocks, and ex-tensor extremities and are bright red,

macu-lan plaques with sharp boundaries. Genen-ally they are transient, but those which per-sist may become fixed and hyperkeratotic. At puberty these lesions may disappear

en-tirely.

The hyperkeratotic lesions have the same

distribution and are also of irregular out-line; but, they are yellow-brown in color and covered with large scales. These usu-ally develop on normal skin and, once pres-ent, tend to persist. Palms and soles may be thickened and hyperkeratotic. Biopsy find-ings are consistent with those of nonbullous CIE.

Extremes of temperature, wind, and emotional stimuli seem to produce the ery-thematous lesions. Some patients have noted the appearance of hyperkeratotie

plaques at sites of scarring or trauma. Vascu-Ian dysplasia has been proposed as the un-denying defect, hut investigation of these patients has not supported the postulate.”

NETHERTON’S SYNDROME

In 1958, Netherton described a

4-year-old child with defects of the skin and hair.4#{176}Only a few patients with this syndrome have been reported, and all have been female.’”

The skin is red and scaly with greater in-volvement of the flexural areas. Nails, teeth, and mucous membranes are normal. The scalp hair is dry, sparse, and fragile and

ranely reaches more than 3 to 4 cm in length during the first decade of life. Eye-brows, lashes, and body hair may also be

affected, but to a milder degree.

On microscopic examination there are nodose swellings at irregular intervals along the hair shaft which resemble a ball-and-socket joint. Clumps of fine, dense black granules have been noted in the hair shaft.

Initially the hair defect was thought to be a unique form of trichorrhexis nodosa

(

an ab-normality in which the swellings along the hair shaft look like interlocking brushes), but, subsequently, the defect has been called trichorrhexis invaginata, a more

ac-cunately descriptive term.

Asthma, urticania, or angioneurotie

edema and positive intradermal responses for the standard food and inhalent allergens complete the syndrome.

RUD’S SYNDROME

The features of Rud’s syndrome are oli-gophrenia, epilepsy, iehthyosis, and infan-tilism. Infantilism appears to be a less

con-stant finding. The following associated anomalies have also been described: partial

gigantism,4’ dwarfism,4’6’ araehnodac-tyly,7 structural defects of the hands and feet, 485o alopeeia,8 nerve deafness,50 and absent or hypoplastic teeth.4648 Eye abnor-malities have included cataracts,47 retinitis pigmentosa,47 strabismus,46,48,bO ptosis, ny-stagmus, and blepharospasm.8

The cutaneous findings vary from mild, generalized, branny desquamation6’7 to a severe ichthyosis resembling snakeskin. #{176}

The extensor surfaces are most often in-volved. Although dermatologic descriptions

are scant, neither erythema nor flexural hy-perkenatoses have been noted. Detailed his-tologie descriptions are not available.

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99S 1CHTHYOSIFORM DE1IMATOSES

reduced glucuronide fraction

(

androsterone and etiocholanolone ), and elevated sulfate fraction

(

mainly dehydnoepiandrosterone)

of the 17-ketostenoids. Lynch, et al.’

re-ported a 19-year-old male with secondary hypogonadism and congenital ichthyosis confirmed by skin and testicular biopsy. Hormonal assay for urinary FSH showed a markedly reduced level, suggesting selec-tive pituitary gonadotropin failure. This

pa-tient was considered to have a different dis-order; however, the endocninologic findings are similar to the previously mentioned case of Rud’s syndrome.’

Few cases of this syndrome have been observed, and none are in documented ped-igrees. Both sexes are affected, and Negro and Caucasian patients have been reported. Until detailed genetic and metabolic data are available, the possibility of ichthyosis coincident with mental retardation and

in-fantilism cannot be excluded.

SJ#{246}GREN-LARSSON SYNDROME

Although two earlier reports of probable

cases Sjogren and Larsson were

the first to study a large number of patients with this syndrome.’4 In 1955, five patients (all with the triad of ichthyosis, oligophre-nia, and spastic paresis) were found in

in-Fic. 4. Bullous congenital ichthyosiform

erythro-derma: extensive vacuolation of the cells in the

mid-epidermis and granular layer and the large, clumped keratohyaline granules are the

pathogno-monic features (H and E).

stitutions for mental defectives in northern Sweden; subsequently, a total of 28 cases

were collected. The authors concluded that

this recessive trait originated from a single mutation in northern Sweden in the mid-fourteenth century. Apart from the cluster of Swedish cases, these are only scattered reports of affected individuals of other na-tional origins. Many are siblings, all with unaffected parents; consanguineous mar-riages occurred in about a third of the

fam-ilies.

The ichthyosis is present at birth and

characterized by generalized, fine scaling with accentuation in the flexures and an as-sociated variable degree of erythroderma. There is hyperkeratosis of the palms and

soles; the hair and nails are normal.

Ectro-P#{176}”is not a significant feature.

Mental deficiency is severe and may Ilecessitate institutional care. Spastic paresis is marked in the legs and less severe or

ab-sent in the arms. The deep tendon reflexes

are increased in involved extremities and Babinski’s sign is present. In some cases, decreased visual activity can he

demon-strated, although tile oph thalmologic

tx-amination is usually normal. Rarely, there

is degeneration of the pigmented epithe-hum of the macula. Dsplasia of tooth

eilamel,6 serrated teeth, and

epilep-sy4’6 have also been reported. Three af-fected members of one family have, in ad-dition, hypertelorism, dermatoglyphic al)-normalities, defective sweating, and speech

defects. 5S

The findings in multiple biopsy speci-mens from six patients include:

hyperkera-toses of the stratum corneum, hypertrophy

and papillomatosis of the epidermis, a

di-minished or absent granular layer, de-creased numbers of sweat glands, and a perivasculan, chronic inflammatory infiltrate in the upper dermis.” Biopsy material from

tw’o of Sjogren and Larsson cases4 and

from several additional cases’’#{176} ShOWS a

normal or increased granular layer but does

not otherwise differ from the foregoing

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llisto-REVIEW ARTICLE 999

logic pattern of nonbullous congenital

ich-thyosiform erythroderma.

Life expectancy was considerably shorter for the affected individuals studied by Sjogren and Larsson54 than for their

unaf-fected siblings. The oligophrenia is appar-ently static, but the spastieity is progressive

and marked by a gradual deterioration of gait and other motor functions. The retinitis was observed in the two oldest patients,

suggesting that this might be a late degen-erative change.’

REFSUM’S SYNDROME

Refsum’s syndrome6i62 consists of an atypical retinitis pigmentosa, chronic

poly-neuritis with progressive paresis of the dis-tal extremities, ataxia and other cerebellar signs, and an elevated cerebrospinal fluid protein. The less constant findings include ichthyosis, perceptive hearing loss, anosmia,

pupillary abnormalities, skeletal defects,

and electrocardiographic changes. Approxi-mately 40 patients, all Caucasian but of varied national origins, have been reported.

The disease is transmitted as an autosomal recessive trait. Familial consanguinity has been established in more than half the cases. Although the onset is usually not until the second or third decade of life, children who are as young as 4 years of age have displayed recognizable signs of the

dis-order.

Affected individuals have increased

con-centration of phytanic acid (3, 7, 11, 15 tet-ramethylhexadecanoie acid

)

in the serum

and tissues.6’ It has been proposed that the biochemical defect in Refsum’s disease may

be an inability to degrade phytanic acid from exogeneous dietary sources because endogenous synthesis of phytanic acid in man is limited or absent. These patients also show a markedly reduced rate of

oxi-dation of orally administered U-’C-phytol

when their serum phytanic acid is

elevated.6’ However, the relationship of the biochemical defects to the signs and

symp-toms of the disease is still unknown. Of in-terest is the involvement of eyes, skin, and

neural elements-all tissues of ectodermal

origin.

A generalized, branny desquamation of dirty-brown scales is the most characteristic

skin change. Thickening oven the knees and elbows has also been described. The eye

shows salt and pepper pigmentation of the retina with atrophy of the ehonoid in the peripheral fundus. Other ocular findings in-elude night blindness, concentric

construe-tion of the visual fields, nystagmus, cata-nacts, miotic pupils, and photophobia. The common manifestations of the peripheral neuropathy are generalized weakness, bilat-eral foot drop, steppage gait, decreased or absent deep tendon reflexes, and symmetri-cal muscle wasting, which is most marked in the lower extremities. Cerebellar signs

are also prominent, but mental deteniora-tion is notably absent. The most

character-istic laboratory finding is the albuminocyto-logic dissociation in the spinal fluid with protein values as high as 600 mg/l00 ml

expeeted.66

The course of the disease is extremely er-ratie and prolonged remissions or stationary phases may occur. Sudden death is not

in-frequent and may be due to failure of the

medullary centers. Dyspnea, dysphagia, vomiting, cough, tachyeardia, and fever are present terminally. Complete heart block has been the final event in some instances.

Eldjarn, et al.67 have demonstnated that elimination of foods containing phytol on phytanic acid can significantly reduce the

serum phytanic acid level. Although the value of dietary therapy has not been es-tablished, such treatment seems indicated in chemically diagnosed eases.

PATHOGENESIS

Although the morphology and histology of the major types of ichthyosis have been clarified, little is known about the patho-genesis of these diseases. The hypertrophie

stratum corneum of ichthyotic skin must represent an imbalance between epidenmal

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either increased production and/or de-creased desquamation of cells. Evidence of altered cellular kinetics has recently been demonstrated. Epidermal mitotic counts are decreased in ichthyosis vulganis but

in-creased in CIE.68 Since in both conditions there is a relatively constant, albeit abnor-mal, accumulation of scale, it was

sug-gested that decreased shedding occurred in ichthyosis vulgaris and increased shedding

occurred in CIE. Increased adhesiveness of

the corneal cells may also be a contributing factor in ichthyosis vulganis. An accelerated epidermal cell transit time (basal layer to granular layer) has been demonstrated in

CIE by autoradiography#{176}#{176} and is further evidence for hyperproliferation of

epider-mal cells in this disease.

An abnormality of skin lipid metabolism in ichthyosis has also been postulated. Ac-quired ichthyosis has been reported in

pa-tients receiving triparanol

(

MER-29) thera-py,70’7’ a drug known to inhibit cholesterol formation at desmosterol. Nicotinic acid

and butyrophenone,72 agents which lower

serum cholesterol levels, have caused simi-lar skin changes. Acquired ichthyosis in Hodgkin’s disease may be associated with hepatic disease,73’74 and some of these pa-tients have had low serum vitamin A and

carotene levels. One case of ichthyosis

(

Sjogren-Larsson syndrome) has been de-scnibed with exudative enteropathy and

steatorrhea.75 Dietary therapy consisting of replacement of normal lipids by medium-chain triglycerides resulted in a cure of both the ichthyosis and the exudative

enter-opathy.

The occurrence of ichthyosis in Refsum’s syndrome, in which accumulation

of a C20 branched-chain fatty acid (phy-tanic acid

)

has been demonstrated, lends further credence to the hypothesis of a dis-ordered lipid metabolism.

The pathogenesis in acquired ichthyo-sisT0’4’76’77 may not be identical to that in the inherited forms; nevertheless, study of such patients may provide insight into the mechanisms by which an iehthyotic skin is produced. Likewise, the mouse mutant

“ich-thyosis”75 migllt serve as a suitable labora-tory model for investigation.

DIAGNOSIS AND TREATMENT

Although patients with obvious

ichthy-osis are not a diagnostic problem, less se-vere involvement, particularly in iehthyosis vulgaris, may be difficult to distinguish from dry skin

(

xerodenma)

.

This difficulty is often compounded since many patients have already been treated with lubricants

and show only minimal scaling. A similar diagnostic dilemma may arise in patients with atopie dermatitis since either xero-denma or ichthyosis vulganis may also be

present. In such situations it may be neces-sary to examine the child after temporarily discontinuing therapy. Other helpful points

in the diagnosis of ichthyosis vulgaris are involvement of the palms and soles, elbows,

and knees and the positive family history. A biopsy showing the foregoing is confirma-tory.

The other types of ichthyosis are usually less difficult to diagnose. Pedigree data, a “dirty” appearance of the affected male due to dark scales on the neck and lateral por-tion of the face, and variable involvement of the flexures are characteristic of sex-linked ichthyosis. More marked hyperkera-tosis in the flexural areas and generalized erythroderma are essential to the diagnosis of either type of CIE. Although flexural

ac-centuation may be difficult to appreciate if

hyperkeratosis is extensive and severe, the

flexures are never involved in iehthyosis vulgaris and are never all involved in sex-linked iehthyosis. Since fading of the eryth-noderma is common with aging, a careful

history is helpful since affected individuals are usually lobster ned at birth and in early

childhood.

There are few conditions which mimic iehthyosis. During the neonatal period

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REVIEW ARTICLE

but there is no scaling and cultures of

bus-ter fluid are usually positive for Group II phage types of Staphylococcus aureus. The

bullae are flaccid, Nikolsky’s sign is posi-tive, and the epidermis peels off in lange sheets. In the olden child, the problem is

usually one of establishing the type of

ichthyosis. A punch biopsy or even an

exci-sional biopsy is a simple and harmless procedure which can be done on an outpa-tient basis and which is usually acceptable

to 1)0th parent and child. This is exceedingly helpful, particularly if the clinical findings are confusing.

The therapy for ichthyosis is restricted

almost entirely to topical preparations. These measures can be very successful for mild or moderately involved patients, but they are usually of little benefit for severely affected individuals. The underlying prinei-pie is hydration of a dry skin and generous application of lubricants to retard evapora-tion and drying. The best procedure is a prolonged daily bath with bath oil followed immediately by application of an ointment, cream, on lotion to the entire body while it is still damp. Generally ointments such as Aquaphon#{176} or petrolatum are more effective because they are relatively occlusive.

Fre-quent supplemental applications of lubri-cant throughout the day will be helpful, but patients should be instructed that prior hydration will always increase their effec-tiveness.

Occasionally a keratolytie agent (e.g.,

salieylic acid

)

incorporated into an oint-ment on oil vehicle can be applied to ex-tremely thick, hyperkeratotic areas. This is particularly effective on the scalp if applied at night and rinsed out in the morning.

Dc-tergen ts and hexachlorophene-containing

soaps should he avoided because they are

very drying. Soap substitutes or super-fat-ted soaps may be used in addition to bath oil. Exposure to winter weather or ex-tremely dry indoor heating should be avoided whenever possible.

0 Duke Laboratories, South Norwalk,

Connecti-cut.

1001

Oral vitamin A has been reported to be effective in certain patients.84’85 The

re-sponse, however, is very variable, and the high dosage required to produce an effect are impractical because of the hazards of

toxicity. Systemic corticosteroids can be lifesaving and are indicated for patients with extensive bullous lesions of CIE.’ This is usually necessary only during the neona-tal period and in early infancy.

Recently a single patient with nonbullous C1E86 and one with bullous C1E47 were treated for several months with daily oral doses of methotrexate with the hope that

this drug would inhibit epidermal mitosis. Both children have shown considerable im-provement in the hyperkenatosis, but no

ef-feet has been noted in the frequency and severity of bullae in the latter patient. The

possible danger of permanent damage to other organ systems mitigates against use of this drug, except in severely handicapped patients. A more rational approach to ther-apy cannot be attempted until the

patho-genesis of these disorders is better

under-stood. To this end, classification and inves-tigation of affected patients is important.

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1002 ICHTHYOSIFORM DEFtMATOSES

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47. Stewart, R. M. : Congenital ichthyosis, idiocy,

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REVIE\V ARTICLE 1003

50. York-Moore, M. E., and Rundle, A. T. : Rud’s syndrome. J. Ment. Deflc. Res., 6:108, 1962. 51. Lynch, H. T., Ozr, F., \lcNutt, \V., Johnson,

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52. Pardo-Costello, V., and Faz, H. :

Ichthv-osis-Little’s disease. Arch. Derm., 26:915, 1932.

53. Laubenthal, F. : Uber (len Erbkreis der Ichthvosis vulgaris. Arch. Derm., 26:915, 1932.

54. Sj#{246}gren, T., and Larsson, T. : A clinical and

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55. Heijer, A., and Reed, W. B.: Sj#{246}gren-Larsson

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57. Link, J. K., and Roldan, E. C.: Mental defi-ciency, spasticity and congenital ichthyosis

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59. Esterly, N. B.: Unpublished data.

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in den Choles-terinestern und anderen Lipoidfraktionen der Organe bei einem Krankheitsfall un-bekannter Genese

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65. Steinberg, D., et al: Refsum’s disease-a

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67. Eldjarn, L., Try, K., Stokke, 0., Munthe-Kaas,

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Small bowel changes in ichthyosis. Lancet, 1:624, 1967.

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ICHTHYOSIFORM DERMATOSES 1004

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1968;42;990

Pediatrics

Nancy B. Esterly