Ichthyoses

Background

This broad category of diseases are hereditary and acquired disorders of epidermal keratinization all characterized by extensive scales. The disorders are classified both by the clinical distribution of the scales as well as by the inheritance patterns. Histologically, most of the disorders show similar features with a thickened stratum corneum.

OUTLINE

Disease Associations

Pathogenesis

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Commonly Used Terms

Internet Links

PATHOGENESIS CHARACTERIZATION

CHYMOTRYPSIN

Expression of stratum corneum chymotryptic enzyme in ichthyoses and squamoproliferative processes.

Johnson B, Horn T, Sander C, Kohler S, R Smoller B.

Department of Dermatology, Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA, Department of Dermatology, Ludwig Maximilian University of Munich, Munich, Germany, and Department of Pathology, Stanford University Medical School, Stanford, CA, USA.

J Cutan Pathol. 2003 Jul;30(6):358-362. Abstract quote
OBJECTIVE: Stratum corneum chymotryptic enzyme (SCCE) is a serine protease, which is thought to play a role in the desquamation of skin via the proteolysis of desmosomes in the stratum corneum. The objective of this study was to investigate the expression of SCCE in ichthyoses and squamoproliferative processes, conditions in which the shedding and replacement of epidermal cells is disrupted.

DESIGN: Tissue samples from cases of Netherton's syndrome, congenital ichthyosiform erythroderma, ichthyosis vulgaris, actinic keratosis, squamous cell carcinoma in situ, and invasive squamous cell carcinoma were examined for expression of SCCE using immunohistochemistry.

MAIN OUTCOME MEASURES: The slides were qualitatively analyzed for the expression of SCCE by a certified dermatopathologist.

RESULTS: In all disease states, we found that the expression of SCCE was absent in areas of parakeratotic stratum corneum of normal thickness. In areas of mixed orthokeratosis and parakeratosis where the stratum corneum was greatly thickened as might correspond clinically to a cutaneous horn, SCCE staining was either absent or focally aggregated without regard to orthokeratosis or parakeratosis. Of note, complete absence of SCCE expression was not observed in any of the cases of ichthyosis examined, nor was there increased expression of SCCE in the atypical cells of the squamoproliferative disorders.

CONCLUSIONS: These results suggest that SCCE is abnormally expressed in skin where epidermal cell kinetics are disrupted due to inherited and acquired defects. Further investigation is needed to determine causality between the abnormal expression of SCCE and the altered cell kinetics in these diseases.

KID SYNDROME

Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome.

Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryynanen M, Jabs EW, Bale SJ, DiGiovanna JJ, Uitto J, Russell L.

Department of Dermatology and Cutaneous Biology and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Am J Hum Genet 2002 May;70(5):1341-8 Abstract quote
Keratitis-ichthyosis-deafness syndrome (KID) is a rare ectodermal dysplasia characterized by vascularizing keratitis, profound sensorineural hearing loss (SNHL), and progressive erythrokeratoderma, a clinical triad that indicates a failure in development and differentiation of multiple stratifying epithelia. Here, we provide compelling evidence that KID is caused by heterozygous missense mutations in the connexin-26 gene, GJB2. In each of 10 patients with KID, we identified a point mutation leading to substitution of conserved residues in the cytoplasmic amino terminus or first extracellular domain of Cx26. One of these mutations was detected in six unrelated sporadic case subjects and also segregated in one family with vertical transmission of KID. These results indicate the presence of a common, recurrent mutation and establish its autosomal dominant nature. Cx26 and the closely related Cx30 showed differential expression in epidermal, adnexal, and corneal epithelia but were not significantly altered in lesional skin. However, mutant Cx26 was incapable of inducing intercellular coupling in vitro, which indicates its functional impairment. Our data reveal striking genotype-phenotype correlations and demonstrate that dominant GJB2 mutations can disturb the gap junction system of one or several ectodermal epithelia, thereby producing multiple phenotypes: nonsyndromic SNHL, syndromic SNHL with palmoplantar keratoderma, and KID. Decreased host defense and increased carcinogenic potential in KID illustrate that gap junction communication plays not only a crucial role in epithelial homeostasis and differentiation but also in immune response and epidermal carcinogenesis.

DISEASE ASSOCIATIONS CHARACTERIZATION

Sjogren-Larsson syndrome Autosomal recessive
Lamellar ichthyosis with spastic paralysis, and mental retardation

KID syndrome Keratitis, Ichthyosis, and Deafness

Conradi's syndrome Chondrodysplasia with ichthyosis and palmar-plantar hyperkeratosis

CHILD SYNDROME Congenital hemidysplasia+ichthyosiform erythroderma+limb defects

Abnormal lamellar granules in a case of CHILD syndrome.

Ishibashi M, Matsuda F, Oka H, Ishiko A.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

J Cutan Pathol. 2006 Jun;33(6):447-53. Abstract quote

Background: A 32-year-old female had cutaneous and musculoskeletal changes consistent with congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome. She was born with the dysplastic, shortened right-sided arm and leg. Erythematous, hyperkeratotic lesion occurred on the trunk initially and extended to the right-sided arm and leg. Almost all area of her right-side body except the head and neck was covered by the erythematous lesion with yellow waxy scales, and the distal end of the rudimentary leg showed a verrucous appearance.

Methods and Results: The histology shared many features with verruciform xanthoma. Electron microscopy revealed vesicular structures in the intercellular spaces of the stratum corneum and vacuoles or vesicular structures in upper prickle cell layer. Some of them can be recognized as abnormal lamellar granules. Within the foamy cells in the papillary dermis, large vacuoles were found.

Conclusion: These findings suggested that abnormal lipid metabolism involving lamellar granules may be responsible to the skin lesion of CHILD syndrome.

Tay's syndrome Close set eyes, beaked nose and sunken cheeks

IBIDS syndrome Ichthyosis+brittle hair+impaired intelligence+decreased fertility+short stature

Multiple sulfatase deficiency Severe neurodegenerative disease, ichthyosis, and signs of mucopolysaccharidosis

Neutral lipid storage disease (Dorfman-Chanarin syndrome) Fatty liver+muscular dystrophy+ichthyosis

Shwachman syndrome Pancreatic insufficiency and bone marrow dysfunction with xerosis and ichthyosis

Refsum's syndrome Autosomal recessive
With cerebellar ataxia, peripheral neuropathy, and retinitis pigmentosa

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

Ichthyosis vulgaris Autosomal dominant-most common variant
Onset early childhood
Extensor surfaces of the arms and legs

X-linked ichthyosis X-linked recessive
Onset at birth or first months
Dirty brown scales involving entire body with sparing of palms and soles
Corneal opacities and mental retardation

Congenital Ichthyosiform erythroderma (CIE)
Also known as non-bullous congenital ichthyosiform erythroderma
May include ichthyosis congenita types I, III, and IV
Autosomal recessive
Erythroderma and fine scales

Lamellar ichthyosis Ichthyosis congenita type II or collodion baby
Autosomal recessive
Large plate like scales involving body and palms and soles

Ichthyosis congenita Alternative classification for the autosomal recessive forms
Type I=CIE
Type II=Lamellar ichthyosis
Type III=CIE, Collodion baby
Type IV=CIE

Bullous ichthyosis Also known as bullous congenital ichthyosiform erythroderma and epidermolytic hyperkeratosis
Autosomal dominant
Severe widespread erythema and blistering which leads to coarse verrucous scales usually in the flexural areas
Six subtypes classified by the presence or absence of palmoplantar erythroderma

Ichthyosis linearis circumflexa Autosomal recessive
Migratory annular and polycyclic erythema with large scaling borderrs on trunk and extremities
Netherton's syndrome with hair shaft abnormalities

Erythrokeratodermia variabilis Autosomal dominant
Infancy with transient erythematous patches and hyperkeratotic plaques often polycyclic or circinate

Harlequin fetus Autosomal recessive
Thick plate-like scales with deep fissures
Incompatible with extra-uterine life

Follicular ichthyosis
Onset during birth or childhood
Abnormal epidermal differentiation occurring in hair follicles
Head and neck
Photophobia and alopecia

Acquired ichthyosis Adult life
Similar to ichthyosis vulgaris
May be associated with underlying disease such as lymphoma, infection, malnutrition, and drugs

Acquired ichthyosis.

Patel N,
Spencer LA,
English JC 3rd,
Zirwas MJ.

Georgetown University School of Medicine, Washington, USA.

J Am Acad Dermatol. 2006 Oct;55(4):647-56. Abstract quote

Acquired ichthyosis (AI) is a nonhereditary cutaneous disorder characterized by dry, rough skin with prominent scaling that involves significant portions of the body. It has been associated with malignancies; autoimmune/inflammatory, metabolic, endocrine, and infectious diseases; and medication use. Most microscopic studies of AI exhibit hyperkeratosis with a reduced or absent granular layer. Because AI has been linked to a variety of conditions, the workup of a patient presenting with this finding can be complex.

We present an update on AI to provide clinicians with direction regarding the assessment and treatment of patients presenting with AI. An algorithm for the evaluation of patients presenting with AI is provided.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
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. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Basic Principles of Disease
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Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
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Surgical Pathology Report
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Special Stains
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How Accurate is My Report?
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Got Path?
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Internet Links

Last Updated October 5, 2006

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Ichthyosis vulgaris	Autosomal dominant-most common variant Onset early childhood Extensor surfaces of the arms and legs
X-linked ichthyosis	X-linked recessive Onset at birth or first months Dirty brown scales involving entire body with sparing of palms and soles Corneal opacities and mental retardation
Congenital Ichthyosiform erythroderma (CIE)	Also known as non-bullous congenital ichthyosiform erythroderma May include ichthyosis congenita types I, III, and IV Autosomal recessive Erythroderma and fine scales
Lamellar ichthyosis	Ichthyosis congenita type II or collodion baby Autosomal recessive Large plate like scales involving body and palms and soles
Ichthyosis congenita	Alternative classification for the autosomal recessive forms Type I=CIE Type II=Lamellar ichthyosis Type III=CIE, Collodion baby Type IV=CIE
Bullous ichthyosis	Also known as bullous congenital ichthyosiform erythroderma and epidermolytic hyperkeratosis Autosomal dominant Severe widespread erythema and blistering which leads to coarse verrucous scales usually in the flexural areas Six subtypes classified by the presence or absence of palmoplantar erythroderma
Ichthyosis linearis circumflexa	Autosomal recessive Migratory annular and polycyclic erythema with large scaling borderrs on trunk and extremities Netherton's syndrome with hair shaft abnormalities
Erythrokeratodermia variabilis	Autosomal dominant Infancy with transient erythematous patches and hyperkeratotic plaques often polycyclic or circinate
Harlequin fetus	Autosomal recessive Thick plate-like scales with deep fissures Incompatible with extra-uterine life
Follicular ichthyosis	Onset during birth or childhood Abnormal epidermal differentiation occurring in hair follicles Head and neck Photophobia and alopecia
Acquired ichthyosis	Adult life Similar to ichthyosis vulgaris May be associated with underlying disease such as lymphoma, infection, malnutrition, and drugs
Acquired ichthyosis. Patel N, Spencer LA, English JC 3rd, Zirwas MJ. Georgetown University School of Medicine, Washington, USA.	J Am Acad Dermatol. 2006 Oct;55(4):647-56. Abstract quote Acquired ichthyosis (AI) is a nonhereditary cutaneous disorder characterized by dry, rough skin with prominent scaling that involves significant portions of the body. It has been associated with malignancies; autoimmune/inflammatory, metabolic, endocrine, and infectious diseases; and medication use. Most microscopic studies of AI exhibit hyperkeratosis with a reduced or absent granular layer. Because AI has been linked to a variety of conditions, the workup of a patient presenting with this finding can be complex. We present an update on AI to provide clinicians with direction regarding the assessment and treatment of patients presenting with AI. An algorithm for the evaluation of patients presenting with AI is provided.

Disease Associations
Pathogenesis
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Commonly Used Terms
Internet Links

PATHOGENESIS	CHARACTERIZATION
CHYMOTRYPSIN
Expression of stratum corneum chymotryptic enzyme in ichthyoses and squamoproliferative processes. Johnson B, Horn T, Sander C, Kohler S, R Smoller B. Department of Dermatology, Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA, Department of Dermatology, Ludwig Maximilian University of Munich, Munich, Germany, and Department of Pathology, Stanford University Medical School, Stanford, CA, USA.	J Cutan Pathol. 2003 Jul;30(6):358-362. Abstract quote OBJECTIVE: Stratum corneum chymotryptic enzyme (SCCE) is a serine protease, which is thought to play a role in the desquamation of skin via the proteolysis of desmosomes in the stratum corneum. The objective of this study was to investigate the expression of SCCE in ichthyoses and squamoproliferative processes, conditions in which the shedding and replacement of epidermal cells is disrupted. DESIGN: Tissue samples from cases of Netherton's syndrome, congenital ichthyosiform erythroderma, ichthyosis vulgaris, actinic keratosis, squamous cell carcinoma in situ, and invasive squamous cell carcinoma were examined for expression of SCCE using immunohistochemistry. MAIN OUTCOME MEASURES: The slides were qualitatively analyzed for the expression of SCCE by a certified dermatopathologist. RESULTS: In all disease states, we found that the expression of SCCE was absent in areas of parakeratotic stratum corneum of normal thickness. In areas of mixed orthokeratosis and parakeratosis where the stratum corneum was greatly thickened as might correspond clinically to a cutaneous horn, SCCE staining was either absent or focally aggregated without regard to orthokeratosis or parakeratosis. Of note, complete absence of SCCE expression was not observed in any of the cases of ichthyosis examined, nor was there increased expression of SCCE in the atypical cells of the squamoproliferative disorders. CONCLUSIONS: These results suggest that SCCE is abnormally expressed in skin where epidermal cell kinetics are disrupted due to inherited and acquired defects. Further investigation is needed to determine causality between the abnormal expression of SCCE and the altered cell kinetics in these diseases.
KID SYNDROME
Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Richard G, Rouan F, Willoughby CE, Brown N, Chung P, Ryynanen M, Jabs EW, Bale SJ, DiGiovanna JJ, Uitto J, Russell L. Department of Dermatology and Cutaneous Biology and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.	Am J Hum Genet 2002 May;70(5):1341-8 Abstract quote Keratitis-ichthyosis-deafness syndrome (KID) is a rare ectodermal dysplasia characterized by vascularizing keratitis, profound sensorineural hearing loss (SNHL), and progressive erythrokeratoderma, a clinical triad that indicates a failure in development and differentiation of multiple stratifying epithelia. Here, we provide compelling evidence that KID is caused by heterozygous missense mutations in the connexin-26 gene, GJB2. In each of 10 patients with KID, we identified a point mutation leading to substitution of conserved residues in the cytoplasmic amino terminus or first extracellular domain of Cx26. One of these mutations was detected in six unrelated sporadic case subjects and also segregated in one family with vertical transmission of KID. These results indicate the presence of a common, recurrent mutation and establish its autosomal dominant nature. Cx26 and the closely related Cx30 showed differential expression in epidermal, adnexal, and corneal epithelia but were not significantly altered in lesional skin. However, mutant Cx26 was incapable of inducing intercellular coupling in vitro, which indicates its functional impairment. Our data reveal striking genotype-phenotype correlations and demonstrate that dominant GJB2 mutations can disturb the gap junction system of one or several ectodermal epithelia, thereby producing multiple phenotypes: nonsyndromic SNHL, syndromic SNHL with palmoplantar keratoderma, and KID. Decreased host defense and increased carcinogenic potential in KID illustrate that gap junction communication plays not only a crucial role in epithelial homeostasis and differentiation but also in immune response and epidermal carcinogenesis.