Epidermolytic Hyperkeratosis

Background

This is both a disease entity and a histologic disease pattern. The diseases are all characterized by compact layers of hyperkeratosis with granular and vacuolar degeneration of the cells within the spinous and granular layers.

OUTLINE

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Treatment

Commonly Used Terms

Internet Links

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

General

Generalized
Bullous ichthyosis

Systemized or linear
Linear epidermal nevus

Palmoplantar
Palmoplantar keratoderma

Solitary
Epidermolytic acanthoma

Multiple discrete
Disseminated epidermolytic acanthoma

Incidental
Focal epidermolytic hyperkeratosis

Follicular
Nevoid follicular epidermolytic hyperkertosis

Mucosal
Epidermolytic leukoplakia

VARIANTS

Phenotypic Heterogeneity in Bullous Congenital Ichthyosiform Erythroderma Possible Somatic Mosaicism for Keratin Gene Mutation in the Mildly Affected Mother of the Proband

Kazuo Nomura, MD, PhD; Kaoru Umeki, MD, PhD; Ichiro Hatayama, PhD; Tadayuki Kuronuma, MD, PhD

Arch Dermatol. 2001;137:1192-1195 Abstract quote

Background
Bullous congenital ichthyosiform erythroderma (BCIE) shows phenotypic variability. An epidermal nevus may represent somatic mosaicism for keratin gene mutation, which produces generalized BCIE in the next generation. This fact provides evidence that a postzygotic mutation can be passed on to the next generation in BCIE. We hypothesized that the same phenomenon occurred in a family with BCIE whose phenotypes were extremely different.

Observations
We studied a 19-year-old boy with severe ichthyosiform erythroderma and prominent palmoplantar hyperkeratosis with digital contracture. In contrast, the proband's mother exhibited only mild ichthyosiform skin, granular verrucous lesions, and less severe streaky palmoplantar hyperkeratosis. Mutation analysis in the proband showed a keratin K1 mutation (N187S, ie, an A-to-G transition at the second position of codon 187, resulting in an asparagine-to-serine substitution). In the mother, the same keratin gene mutation was recognized, but only faintly in the leukocyte DNA, indicating that the amount of the mutated allele in leukocyte DNA was very low compared with that from the proband.

Conclusions
We speculate that the mildly affected mother showed keratin 1 gene mosaicism, and that the BCIE phenotype had been transmitted in a severe form through a mechanism that passes the keratin gene mutation to the next generation. These results suggest that mild forms of BCIE may actually represent extensive epidermal nevi/keratin gene mosaicism.

LOCALIZED

Localized epidermolytic hyperkeratosis of the female external genitalia.

Swann MH, Pujals JS, Pillow J, Collier SL, Hiatt K, Smoller BR.

University of Arkansas for Medical Sciences, Dermatology, Little Rock, AR, USA.

J Cutan Pathol. 2003 Jul;30(6):379-81 Abstract quote
BACKGROUND: Epidermolytic hyperkeratosis (EH) is most commonly associated with the diffuse involvement of congenital ichthyosiform erythroderma, but can also be found in a localized pattern. Localized EH is rare, but mucocutaneous lesions have been been identified, most commonly in the mouth.

METHODS: We observed a 58-year-old African-American female who noted spots on her genitalia for approximately 2 years. The lesions were increasing in size, darkening, and had become pruritic and sore over the past 6 months.

RESULTS: Physical examination revealed seven scattered, tan to brown, verrucoid papules on the labia and mons pubis, resembling condylomata acuminata or Bowenoid papulosis. Biopsy of a single labial papule revealed epidermal acanthosis, compact hyperkeratotic papillomatosis, perinuclear clear zones, granular keratohyalin clumping, hypergranulosis, and dyskeratosis resulting in intracellular eosinophilic globules, all characteristic of EH.

CONCLUSIONS: Because of the rarity of localized genital EH and similar appearance to common diagnoses, clinical confusion may occur without biopsy.

TREATMENT CHARACTERIZATION

ACITRETIN

An appraisal of acitretin therapy in children with inherited disorders of keratinization.

Lacour M, Mehta-Nikhar B, Atherton DJ, Harper JI.

Department of Dermatology, Great Ormond Street Hospital for Children, London, U.K.
Br J Dermatol 1996 Jun;134(6):1023-9 Abstract quote
Retinoid therapy represents the treatment of choice for severe inherited disorders of keratinization.

This paper reviews our experience of acitretin, compares acitretin with etretinate and defines guidelines for treatment. Forty-six children have received acitretin since 1992 in our hospital: 29 children had either lamellar ichthyosis (nine), non-bullous ichthyosiform erythroderma (five), bullous ichthyosiform erythroderma (four), Sjogren-Larsson syndrome (three) or another rare condition (eight). The other 17 children who had psoriasis (16) and extensive viral warts (one), were excluded. Data on efficacy and tolerability of retinoid therapy were available for all but one patient. The cumulative follow-up was 472 months for acitretin. The mean (+/- standard deviation) optimal dosage for acitretin was 0.47 +/- 0.17 mg/kg per day, and this did not significantly differ between disorders. The overall improvement was considerable, with only three patients responding poorly. Mild to moderate mucocutaneous dryness was frequent. Minor abnormalities of liver function tests (four patients) and triglycerides (one patient) never led to changes of therapy. Irreversible side-effects did not occur. Acitretin therapy for children with inherited keratinization disorders is best started at 0.5 mg/kg per day. It represents a safe and effective treatment, provided that the minimal effective dose is maintained and that side-effects are carefully monitored.

When switching from etretinate to acitretin, a 20% reduction is recommended if the etretinate dose is over 0.75 mg/kg per day or if side-effects are dose limiting. Otherwise the same dose can be used.

ALPHA HYDROXY ACID

An evaluation of the effect of an alpha hydroxy acid-blend skin cream in the cosmetic improvement of symptoms of moderate to severe xerosis, epidermolytic hyperkeratosis, and ichthyosis.

Kempers S, Katz HI, Wildnauer R, Green B.

Minnesota Clinical Study Center, Fridley 55432-3313, USA.
Cutis 1998 Jun;61(6):347-50 Abstract quote
A number of genetic, intrinsic, and extrinsic factors can cause conditions of problem dry skin, marked by unusual dryness, rough texture, and extreme flaking and scaling, that are generally not controlled by conventional moisturizers.

A study was undertaken to evaluate the safety and efficacy of two novel alpha hydroxy acid (AHA)-containing creams in reducing the appearance and symptoms of problem dry skin on subjects with a range of dry skin conditions, including xerosis, epidermolytic hyperkeratosis, and ichthyosis. Twenty subjects completed a course of treatment with either regular or extra strength AHA-blend cream on a test site, compared with a currently marketed, non-AHA moisturizing lotion on a control site. Subjects were treated for 4 weeks, with clinical evaluations performed at weeks 0, 2, and 4. The test for mulations reduced symptoms and improved cosmetic appearance following 2 weeks of use, with continued improvement following 4 weeks of use.

Improvements were significant compared to baseline and compared to sites treated with the control lotion. Some patients experienced mild to moderate local adverse effects; all subjects were able to continue using the test product for the duration of the study.

ISOTRETINOIN

Treatment of ichthyosis with isotretinoin.

Baden HP, Buxman MM, Weinstein GD, Yoder FW.
J Am Acad Dermatol 1982 Apr;6(4 Pt 2 Suppl):716-20 Abstract quote
A multicenter study of the effectiveness of 13-cis-retinoic acid (isotretinoin) in lamellar ichthyosis and epidermolytic hyperkeratosis has been conducted. A dose of the drug which produced maximum clearing with minimum side effects was chosen; this varied among different patients, the mean dose being about 2 mg/kg/day.

Almost all of the patients in both groups were clearly improved, as evaluated both by the physicians and the patients. The degree of improvement seemed higher in the group of patients with lamellar ichthyosis.

TIGASON

Long-term oral treatment of two pronounced ichthyotic conditions: lamellar ichthyosis and epidermolytic hyperkeratosis with the aromatic retinoid, Tigason (RO 10-9359).

El-Ramly M, Zachariae H.
Acta Derm Venereol 1983;63(5):452-6 Abstract quote
Five patients suffering from lamellar ichthyosis and 3 from epidermolytic hyperkeratosis (previously called non-bullous and bullous congenital ichthyosiform erythroderma) were treated from 11 to 52 months with the synthetic aromatic retinoid Tigason (RO 10-9359). In all cases of lamellar ichthyosis the results were judged as good to excellent, while none of the patients with epidermolytic hyperkeratosis gave more than a slight response.

The reason for the poorer results in the latter condition was that effective therapeutic dosages in relation to ichthyosis invariably produced increased blistering. These and other side effects such as cheilitis, mild dryness of mucous membranes, slight hair loss, and pruritis, in no case necessitated discontinuation of the drug.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

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Commonly Used Terms
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Last Updated 7/30/2003

TREATMENT	CHARACTERIZATION
ACITRETIN
An appraisal of acitretin therapy in children with inherited disorders of keratinization. Lacour M, Mehta-Nikhar B, Atherton DJ, Harper JI. Department of Dermatology, Great Ormond Street Hospital for Children, London, U.K.	Br J Dermatol 1996 Jun;134(6):1023-9 Abstract quote Retinoid therapy represents the treatment of choice for severe inherited disorders of keratinization. This paper reviews our experience of acitretin, compares acitretin with etretinate and defines guidelines for treatment. Forty-six children have received acitretin since 1992 in our hospital: 29 children had either lamellar ichthyosis (nine), non-bullous ichthyosiform erythroderma (five), bullous ichthyosiform erythroderma (four), Sjogren-Larsson syndrome (three) or another rare condition (eight). The other 17 children who had psoriasis (16) and extensive viral warts (one), were excluded. Data on efficacy and tolerability of retinoid therapy were available for all but one patient. The cumulative follow-up was 472 months for acitretin. The mean (+/- standard deviation) optimal dosage for acitretin was 0.47 +/- 0.17 mg/kg per day, and this did not significantly differ between disorders. The overall improvement was considerable, with only three patients responding poorly. Mild to moderate mucocutaneous dryness was frequent. Minor abnormalities of liver function tests (four patients) and triglycerides (one patient) never led to changes of therapy. Irreversible side-effects did not occur. Acitretin therapy for children with inherited keratinization disorders is best started at 0.5 mg/kg per day. It represents a safe and effective treatment, provided that the minimal effective dose is maintained and that side-effects are carefully monitored. When switching from etretinate to acitretin, a 20% reduction is recommended if the etretinate dose is over 0.75 mg/kg per day or if side-effects are dose limiting. Otherwise the same dose can be used.
ALPHA HYDROXY ACID
An evaluation of the effect of an alpha hydroxy acid-blend skin cream in the cosmetic improvement of symptoms of moderate to severe xerosis, epidermolytic hyperkeratosis, and ichthyosis. Kempers S, Katz HI, Wildnauer R, Green B. Minnesota Clinical Study Center, Fridley 55432-3313, USA.	Cutis 1998 Jun;61(6):347-50 Abstract quote A number of genetic, intrinsic, and extrinsic factors can cause conditions of problem dry skin, marked by unusual dryness, rough texture, and extreme flaking and scaling, that are generally not controlled by conventional moisturizers. A study was undertaken to evaluate the safety and efficacy of two novel alpha hydroxy acid (AHA)-containing creams in reducing the appearance and symptoms of problem dry skin on subjects with a range of dry skin conditions, including xerosis, epidermolytic hyperkeratosis, and ichthyosis. Twenty subjects completed a course of treatment with either regular or extra strength AHA-blend cream on a test site, compared with a currently marketed, non-AHA moisturizing lotion on a control site. Subjects were treated for 4 weeks, with clinical evaluations performed at weeks 0, 2, and 4. The test for mulations reduced symptoms and improved cosmetic appearance following 2 weeks of use, with continued improvement following 4 weeks of use. Improvements were significant compared to baseline and compared to sites treated with the control lotion. Some patients experienced mild to moderate local adverse effects; all subjects were able to continue using the test product for the duration of the study.
ISOTRETINOIN
Treatment of ichthyosis with isotretinoin. Baden HP, Buxman MM, Weinstein GD, Yoder FW.	J Am Acad Dermatol 1982 Apr;6(4 Pt 2 Suppl):716-20 Abstract quote A multicenter study of the effectiveness of 13-cis-retinoic acid (isotretinoin) in lamellar ichthyosis and epidermolytic hyperkeratosis has been conducted. A dose of the drug which produced maximum clearing with minimum side effects was chosen; this varied among different patients, the mean dose being about 2 mg/kg/day. Almost all of the patients in both groups were clearly improved, as evaluated both by the physicians and the patients. The degree of improvement seemed higher in the group of patients with lamellar ichthyosis.
TIGASON
Long-term oral treatment of two pronounced ichthyotic conditions: lamellar ichthyosis and epidermolytic hyperkeratosis with the aromatic retinoid, Tigason (RO 10-9359). El-Ramly M, Zachariae H.	Acta Derm Venereol 1983;63(5):452-6 Abstract quote Five patients suffering from lamellar ichthyosis and 3 from epidermolytic hyperkeratosis (previously called non-bullous and bullous congenital ichthyosiform erythroderma) were treated from 11 to 52 months with the synthetic aromatic retinoid Tigason (RO 10-9359). In all cases of lamellar ichthyosis the results were judged as good to excellent, while none of the patients with epidermolytic hyperkeratosis gave more than a slight response. The reason for the poorer results in the latter condition was that effective therapeutic dosages in relation to ichthyosis invariably produced increased blistering. These and other side effects such as cheilitis, mild dryness of mucous membranes, slight hair loss, and pruritis, in no case necessitated discontinuation of the drug.

Gross Appearance and Clinical Variants
Histopathological Features and Variants
Treatment
Commonly Used Terms
Internet Links

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
Generalized	Bullous ichthyosis
Systemized or linear	Linear epidermal nevus
Palmoplantar	Palmoplantar keratoderma
Solitary	Epidermolytic acanthoma
Multiple discrete	Disseminated epidermolytic acanthoma
Incidental	Focal epidermolytic hyperkeratosis
Follicular	Nevoid follicular epidermolytic hyperkertosis
Mucosal	Epidermolytic leukoplakia
VARIANTS
Phenotypic Heterogeneity in Bullous Congenital Ichthyosiform Erythroderma Possible Somatic Mosaicism for Keratin Gene Mutation in the Mildly Affected Mother of the Proband Kazuo Nomura, MD, PhD; Kaoru Umeki, MD, PhD; Ichiro Hatayama, PhD; Tadayuki Kuronuma, MD, PhD	Arch Dermatol. 2001;137:1192-1195 Abstract quote Background Bullous congenital ichthyosiform erythroderma (BCIE) shows phenotypic variability. An epidermal nevus may represent somatic mosaicism for keratin gene mutation, which produces generalized BCIE in the next generation. This fact provides evidence that a postzygotic mutation can be passed on to the next generation in BCIE. We hypothesized that the same phenomenon occurred in a family with BCIE whose phenotypes were extremely different. Observations We studied a 19-year-old boy with severe ichthyosiform erythroderma and prominent palmoplantar hyperkeratosis with digital contracture. In contrast, the proband's mother exhibited only mild ichthyosiform skin, granular verrucous lesions, and less severe streaky palmoplantar hyperkeratosis. Mutation analysis in the proband showed a keratin K1 mutation (N187S, ie, an A-to-G transition at the second position of codon 187, resulting in an asparagine-to-serine substitution). In the mother, the same keratin gene mutation was recognized, but only faintly in the leukocyte DNA, indicating that the amount of the mutated allele in leukocyte DNA was very low compared with that from the proband. Conclusions We speculate that the mildly affected mother showed keratin 1 gene mosaicism, and that the BCIE phenotype had been transmitted in a severe form through a mechanism that passes the keratin gene mutation to the next generation. These results suggest that mild forms of BCIE may actually represent extensive epidermal nevi/keratin gene mosaicism.
LOCALIZED
Localized epidermolytic hyperkeratosis of the female external genitalia. Swann MH, Pujals JS, Pillow J, Collier SL, Hiatt K, Smoller BR. University of Arkansas for Medical Sciences, Dermatology, Little Rock, AR, USA.	J Cutan Pathol. 2003 Jul;30(6):379-81 Abstract quote BACKGROUND: Epidermolytic hyperkeratosis (EH) is most commonly associated with the diffuse involvement of congenital ichthyosiform erythroderma, but can also be found in a localized pattern. Localized EH is rare, but mucocutaneous lesions have been been identified, most commonly in the mouth. METHODS: We observed a 58-year-old African-American female who noted spots on her genitalia for approximately 2 years. The lesions were increasing in size, darkening, and had become pruritic and sore over the past 6 months. RESULTS: Physical examination revealed seven scattered, tan to brown, verrucoid papules on the labia and mons pubis, resembling condylomata acuminata or Bowenoid papulosis. Biopsy of a single labial papule revealed epidermal acanthosis, compact hyperkeratotic papillomatosis, perinuclear clear zones, granular keratohyalin clumping, hypergranulosis, and dyskeratosis resulting in intracellular eosinophilic globules, all characteristic of EH. CONCLUSIONS: Because of the rarity of localized genital EH and similar appearance to common diagnoses, clinical confusion may occur without biopsy.