CASE REPORTSPediatric Dermatology Vol. 14 No. 5 355-358, 1997
Autosomal Recessive Inheritance ofErythrokeratoderma Variabilis
D. K. B. Armstrong, MRCP,* T. H. Hutchinson, M.D.,* M. Y. Walsh, FRCPath,t andJ. C. McMillan, FRCP*
Departmetits of *Dennatology atid fPathology. Belfast City Hospital, Belfast. Northern Ireland
Abstract: Erythrokeratoderma variabilis is a rare genodermatosis con-ventionally regarded as autosomal dominant in inheritance. We describethe clinical features and light and electron microscopic findings in twoaffected siblings bom to unaffected parents and suggest an autosomalrecessive mode of inheritance in this family. We also briefly review theliterature on this disorder.
The term erythrokeratoderma variabilis (EKV) wasfirst used by Mendes da Costa (1) and describes theoccurrence of bizarre, figurate. sharply demarcated ery-thematous patches showing variability in pattern and lo-cation over minutes, hours, or days. In association withsuch lesions the affected individual develops relativelyfixed areas of erythema and hyperkeratosis u'ith a par-ticular propensity to affect extensor sites. Inheritance isusually simple autosomal dominant, although sporadiccases are not infrequently reported. We describe two af-fected siblings bom to unaffected parents, suggesting au-tosomal recessive inheritance in this family.
CASE REPORTS.A male infant developed a sharply demarcated, macular,er\'thematous patch on his left cheek at the age of 3 days.The margins were geographic and varied in outline overhours to days. He subsequently developed similar er\-thematous patches on his right cheek, trunk, buttocks,and the extensor aspects of his limbs. The.se showedsimilar capricious borders and variability and were notassociated with any apparent distress. At the age of 9months, sharply demarcated plaques of both hyperkera-tosis and ervthema were noted in a svmmeti'ical distri-
bution on the face, trunk, buttocks, and limbs (Fig. 1).Once again the borders of the plaques were sharply de-marcated and geographic in outline. The.se hyperkeratot-ic plaques were relatively fixed but did show evidence ofvariability over weeks to months, a phenomenon moremarked with the truncal placjues. Cold conditiotis exac-erbated both morphologic components, but emotionalupset or heat had no significant effect. Sunlight appearedto ameliorate the eruption. With increasing age there vvasa marked diminution in the erythematous patches and anincreasing predominance of hyperkeratotic plaques.
This young boy's sister was born 5 years later and hadsimilar variable, deeply erythematous, discrete, geo-graphic patches on her face, trunk, and limbs at 4 days ofage. Hyperkeraloiic, cr\'ihematous plaques with a dis-tinctly figurate outline developed at 8 months of age andhave shown a similar tendency to predominate overmacular erythematous lesions with increasing age (Fig.2). Once again cold conditions aggravated the conditionwhile sunlight appeared to be helpful.
In both siblings there were no other significant medi-cal problems and mucous membranes, hair, nails, andteeth were entirely normal. Palmoplantar keratodennawas not pre.sent in either child.
Diagnostic punch biopsy specimens were taken from
Adrires.s cnrre.sponiicnce to IDr. D. K. B .^nnsirong. Depiirlmeni ofDermalcilogy. Wing D. Belfast City Hospital. I.isbum Road, BelfastHP) 7AB. Northern Ireland. United Kitiadoin.
356 Pediatric Dermatology Vol. 14 No. 5 September/October 1997
Figure 1. Figurate plaques of erythema and hyperkerato-sis on trunk of older brother.
Figure 2. Discrete hyperkeratotic plaques with geo-graphic outline on trunk of younger sister.
both children from hyperkeratotic plaques involving but-tock skin. E.\amination by light microscopy and electronmicroscopy .showed essentially identical feature.s in eachchild. Light microscopy showed marked orthohypcrkera-tosis with prominence of the underlying stratum granu-losum and moderate acanthosis. A scant tnononuclearperiva.scular infiltrate wa.s present in the papillary der-mis. There were no dyskeratotic cells visible in the epi-dermis (Fig. .1). Electron microscopy confirmed themarked thickening of the comificd layer but, of note, didnot show diminution of the number of keratinosomes inthe stratum granulosum. There wa.s no clumping of tono-filaments and the mitochondria were not swollen.
A detailed family histor\' revealed no similar cutane-ous condition in either parent or their siblings or parents.There v\'as no history of con.sanguinity. Cutaneous ex-amination confirmed the nomial findings in these indi-viduals.
Both children have been treated with simple emol-lients. In view of the asymptomatic nature of the erup-tions and their young age. retinoids have not been used todate.
Figure 3. Histopathology of hyperkeratotic plaque on but-tock of older brother demonstrated hyperkeratosis, promi-nence of the stratum granulosum, and acanthosis. (He-matoxylin and eosin; magnification 250x.)
EKV is a rare genodennatosis with two distinctive mor-phologic components. The first is the occurrence of bi-zarre, figurate. sharply defined, erythematous patches
Armstrong ct al: Erythrokeratixierma Variabilis 357
that change their shape and distribution within minutes,hours, or days. The second is the occurrence of morepersistent plaques of hyperkeratosis with striking geo-graphic outlines. Such plaques may arise independentlyon previously normal skin or on areas of persistent er\'-ihema. .Areas particularly involved include the face, but-tocks, and e.xtensor a.spects of the litnbs, usually in asymmetrical manner. The variability in position and out-line is most marked for the erythrodennic component butis present to a lesser degree in the hyperkeratotic areas.The two patients we describe conform well to these clini-cal features. EKV shows marked variahility in expres-sion, and either morphologic component may predomi-nate. As in both our patients, the erythrodermiccomponent may diminish in intensity or even disappearwith time (2). Cold, wind, and emotional upset are com-monly reported as aggravating factors, but sunlight hasnot been previously reported as a significant ameliorat-ing factor. The increase in scaling noted during winter inthese siblings may in part reflect increa.sed xerosis due toclimatic conditions. Lesions are present at birth in up toone-third of patients, with the tnajority of the remainderdeveloping signs within the first year. The plaques areusually asymptomatic or associated with mild pruritusonly. There may he varv'ing degrees of palmoplanlarkcratixlerma in association with the condition, but themucous membranes, hair, nails, and teeth are invariablynormal- There is also a striking absence of reported as-sociated congenital defects.
The most striking histologic features of hyperkeratoticlesions under light microscopy are marked orthohy-perkeratosis and irregular acanthosis with varyingdegrees of papillomatosis and suprapapillary thinning.The stratum granulosum is usually two to three celllayers thick. In many cases there is a scant lympho-histiocytic perivascular infiltrate in the papiilar\' dermis(3). Variable capillary dilatation in the papillaiy der-mis has also been reported (4). One report describeddistinctive dyskeratotic cells in the stratum granulosumand upper spinous layer (4). Electron microscopic studieshave not shown consistent findings. Several studieshave documented a marked reduction in the number ofkeratino.i;onies in cells of the stratum granulosum andupper spinous layer (3,4). Systemic treatment withisotretinoin induced not only a clinical response but alsoa restoration of normal numbers of epidermal keratino-somes (4). In contrast, several other ultrastructural stud-ies have failed to demonstrate any reduction in keiatino-some numbers in lesional epidermis (5,6). Thedyskeratotic cells demonstrated under light microscopyin one report were shown to contain large amounts ofclumped perinuclear tonolilaments under electron mi-croscopy. Their appearance was unchanged by retinoid
therapy (4). Ultrastructural studies have also shown de-creased numbers or an absence of epidermal Langerhanscells in lesional hyperkeratotic epidennis and increa.sednumbers of unmyelinated nerve fibres in the papillarydennis (3,4,7). Others have failed to detect such changes,and their relevance to the pathogenesis of EKV remainsunclear (8).
EKV is a chronic condition with a propensity for hy-perkeraioiic plaques to increase in extent and severityuntil puberty, thereafter remaining fairly stable (2). Er)'-thematous patches may become less prominent with in-creasing age. Hormonal influences have been suggested,with reports of resolution of lesions at menopause anddeterioration during pregnancy or with estrogen-containing contraceptive preparations (9).
Treatment with simple emollients and topical kerato-lytic preparations usually results in some improvement inthe degree of hyperkeratosis. Both topical and systemicretinoids have also been demonstrated to producemaiked or complete clearance in most but not all patients(10-13). In .some cases clearance of hyperkeratotic le-sions was more evident with only partial clearing of mi-gratory er>thematous patches. Rapid relapse on discon-tinuation of retinoids is the rule (10.12). In view of thepotential toxicity of such agents, the chronic course ofthe condition, the young age of our patients, and theessentially asymptomatic nature of the eruption, weopted not to use such therapy in these two children. Thesignificant cosmetic and psychological effects that such acondition may ha\'e, however, may necessitate use al alater date.
The genetic defect and pathogenesis underlying EKVremains unclear. The vast majority of reported cases andlarge pedigrees to date suggest a simple autosomal dom-inant mode of inheritance w ith variability of expression(9.14-16). The presence of this condition in two .siblingsin tbe family reported here, in the absence of a history orclinical signs in any previous generation, would be con-sistent with autosomal recessive inheritance. This beingthe ca.se, the implication is that their offspring will becarriers but will not manifest the condition. .Autosomalrecessive inheritance of EKV has only ver\' rarely beenreported (17). McFarlane et al. (5) reported two sisters,one with features of EKV and the other with features ofprogressive symmetrical erythrokeratoderma (PSEK).whose parents were unaffected. Ultrastructural findingsin both patients were identical and it was suggested thatEKV and PSEK may be different manifestations of asingle condition.
There are several other possihle explanations for ap-parently different modes of inheritance of a single con-dition in different kindreds. The first and perhaps mostcommon is the presence of incomplete penetrance or
3.'i8 Pediatric Dermatology Vol. 14 No. 5 September/October 1997
variable expressivity, whereby one parent carries tlie ab-normal gene but manifests only verj' subtle featureswhich are overlooked until their offspring present with amore typical, clinically apparent phenotype. Careful cu-taneous examination of this kindred failed to documentany abnormal findings in previous generations, A secondpossible mechanism is the phenomenon of genetic het-erogeneity in which mutations in two or more differentgenes can be associated with indistinguishable pheno-types. The mode of inheritance at each locus may in turnvary. Finally, gonadal mosaicism may result in apparentor "pseudo-recessive" inheritance and has been noted indi.sorders such as osteogenesis imperfecta. The geneticUKUS or loci for EKV remain to be established, but link-age analy,sis in a large Dutch kindred showed linkagew ith the Rhesus locus on the shon arm of chromosome 1(14). In view of the variability in inheritance patternsreported and the overlap of both clinical and bistologicfindings among the erj'throkeratodermas, it may be thataccurate classification of this spectrum of diseases ispossible only when the underlying molecular defects arediscovered.
Most authors regard EKV as a "retention-type byper-keratosis" (3.8), In support of this, autoradiographicstudies ,show no evidence of increased epidermal prolif-eration (18), .A role for the reduced number of observedkeratino,somes in hyperkeraiotic lesions in potentiatingreduced desquamation has been proposed by the sameauthors but remains to be established, .An immunohisto-chemical study also demonstrated basal cell type keratinreactivity in lesional stratum comeum. leading to specu-lation on its role in increasitig intercellular cohesion (8),The expression normalized with the u.se of etretinate.Others have proposed an abnormal systemic vascular di-latation disorder or a vasomotor disorder with vasculardilatation leading to secondary hyperkeratosis akin toangiokeratomas. This .seems much less likely.
In summary, we describe two children with both clini-cal and histologic features of EKV in whom a detailedfamily history showed no previous evidence of the con-dition, thereby supporting an autosomal recessive modeof inheritance. This is in contrast to almo.st aD previouslyreported cases in which simple autosomal dominant in-heritance or spontaneous mutation were proposed.
1. Mendes da Costa S, Er>'thro-et keratoderma variabilis in amother and daughter, Acta Dertnatol Venereol (Stockh)1925;6:255-26I.
2. Brown J, Kierland RR. Erythrokeratodennia variahilis.Arch Dermatol 1966;93:194-2OI.
3. Vandersteen PR, MuUer SA, Erhythrokeratodermia vari-abilisan enzyme histochemical and ultrastructural study..^rch Dermatol 1971:103:362-370.
4. Rappaport P, Goldes J,A, Goltz RW. Er>ahrokeratodenniavariabilis treated with isotretinoin. .Arch Dermatol 1986;122:441^45.
5. MacFarlane .'WV, Chapman SJ, Verbor JL. Is er\throkera-tixietma one disorder? A clinical and ultrastructural studyof two siblings. BrJ Dermatol 1991,124:487-491,
6. Jurecka W, Erhythrokeratodeniiia variabilis. Arch Denna-tol 1986; 122:1356.
7. Van der Schroeft JG, Ruiter DJ, Bin,s GT. Epidermal Lang-erhans cells ill erythrokcratodermia variabilis. Arch Der-matol Res 1982;274:339-.348.
8. McFadden N, Oppedal BR, Ree K, Brandtzaeg P. Eryth-rokeratodennia variabilis: immunohistochemical and ultra-structural studies of the epidennis. .Acta Dermatol Vene-reol (Stockh) 1987;67:284-288.
9. Gcwirtzman GB. Winkler NW. Dobson RI.. Erylhrokera-todermia variabilis: a family study. Arch Dermatol 1978:114:259-261.
10. Van de Kerkhof PCM, Steijien PM. van Dooren-GreebeRJ, Happle R, ,Acitrctin in the treatment of erythrokerato-dennia variabilis. Dermatoligica 1990; 181:330-333.
11. Van der Wateren .AR, Cormane RH, Oral retinoic acid astherapy for er\throkeiatoderma variabiiis, J Dernialol1977,97:8.3-85'
12. Marks R, Finlay .\Y. Holt PJ, Severe disorders of kerati-nization: effects of treatment with 1 igason (etretinate). BrJ Dennatol 1981;104:667-673.
13. Knipe RC, Flowers FP, Johnson FR. Debusk FL, Ratno.s-Caro FA. Erythrokeratodenna variabilis: case repo...