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Clinical Updates

Christine Bodemer, MD PhD

Inherited Ichthyosis: New Advances, New Objectives

Christine Bodemer

Tuesday, December 04, 2007

Ichthyoses have been defined clinically by the presence of visible scales, with a thickened stratum corneum being present histopathologically in most cases. Therefore, the clinical diagnosis of ichthyosis is easy. The characteristics of the scales (fine or thick, dark or light); a blistering phenotype; the surface involved (localized or diffuse); the age of onset (neonatal: collodion baby, Harlequin fetus phenotype, lamellar ichthyosis, bullous or non-bullous ichthyosiform erythroderma, other ichthyosiform manifestations; or not neonatal); the association with marked inflammation (erythroderma or not), hair (hair defect, alopecia, hair shaft defect), or nail abnormalities; the association with predominant extra cutaneous manifestations (neurological symptoms, growth failure, photophobia, keratitis, deafness); family history; and the existence (or not) of consanguinity are essential to determine the best treatment.

At the end of this first clinical step, it's often possible to classify the patient in non-syndromic or syndromic ichthyoses. However, the clinical phenotype may vary with environmental factors, particularly in the first years of life. The congenital non-bullous ichthyosiform erythroderma (NBIE) and the lamellar ichthyosis (LI) are particularly difficult to be classified. Indeed, these cutaneous phenotypes can be observed in non-syndromic and syndromic inherited ichthyosis. The non-syndromic forms are autosomal-recessive in most cases. Some authors consider only the term of lamellar ichthyosis, as NBIE and LI could belong to the same clinical spectrum with large, dark and plate-like scales over most of the skin in LI (at the polar end of the spectrum), and prominent diffuse erythroderma with diffuse fine white scales in NBIE (at the other polar end of the spectrum).1 Many patients exhibit intermediate phenotypes, and changes with overlapping features can be observed in the same patient over time. Therefore, the clinical features observed at a medical visit are often not sufficient to define a precise subtype of congenital non-bullous ichthyosis. Moreover, overlapping genotypes have now been described among the two clinical subtypes (see Tables 1 and 2). Thus, it might be better to consider NBIE and LI as "variations of a single but closely related group of disorders." 2

Understanding that, if inherited ichthyoses have been initially classified by clinical features and inheritance patterns, enables a better understanding of the pathophysiology. In addition, the elucidation of the molecular mechanisms would permit a better classification of these genetic disorders and better treatment.

Genetic Bases and Physiopathology: Recent Advances

As a result of the active molecular research today, around 15 genes have been identified. In Tables 1 and 2, recent advances in the molecular and biological research are presented. These tables include the main inherited ichthyoses but are not exhaustive.

Table 1: Main non-syndromic inherited ichthyoses 

Phenotype ichthyosis

Gene(s) responsible /  Gene product

Inheritance pattern

Ichthyosis vulgaris

FLG/filaggin

AD

X-linked recessive ichthyosis

STS/steroid sulphatase

RXLI

Bullous ichthyosiform erythroderma

KRT1, KRT10/ Keratin 1 or 10

AD

Ichthyosis bullosa of Siemens

KRT2e/ Keratin 2e

AD

Ichthyosis hystrix Curth-Macklin

KRT1/ Keratin 1

AD

Lamellar ichthyosis (LI)

and/or

Non-bullous ichthyosiform erythroderma (NBIE)

TGM1/ Transglutaminase 1

ALOXE3/Lipoxygenase E3,

ALOX12B/ Lipoxygenase12B

Ichthyin/membrance receptor

ABCA12/ lamellar body lipid transporter

AR

AR

AR

AR

Harlequin fetus

ABCA12/ lamellar body lipid transporter

AR

Autosomal dominant LI

Unknown

AD

 

 

Table 2:  Main syndromic ichthyoses

Phenotype ichthyosis

Extra-cutaneous manifestations

Gene responsible / gene product

Diagnostic tests

2-a Defect in lipid metabolism

2-a Defect in lipid metabolism

2-a Defect in lipid metabolism

2-a Defect in lipid metabolism

X-linked recessive ichthyosis

Mental retardation

Hypogonadism

anosmia

STS/steroid sulphatase

Decreased sulphatase activity in cells cultures (fibroblasts, leucocytes)

Elevated plasma cholesterol sulphate levels

Refsum's disease

AR

Retinitis pigmentosa

Peripheral neuropathy

ataxia

PAHX/Phytanol-CoA alpha-hydroxylase

Elevation of plasma phytanic acid levels

Dorfman Chanarin

syndrome

AR

Hepatomegaly

Myopathy

Cataracts

Neurosensory deafness

CGI-58/CG1-58: lipase family

Presence of lipid-containing vacuoles in circulating granulocytes (peripheral smear)

Sjögren Larsson' syndrome

AR

Mental retardation

Spasticity

Macular dystrophy of the retina

Pruritus

FALDH/ Fatty aldehyde dehydrogenase

Decreased fatty aldehyde dehydrogenase activity (culture of fibroblasts)

Gaucher's syndrome type 2

AR

Collodion baby

Neurological involvement

Hypertonicity

Choking spells

Strabismus

Joint contractures

Thrombocytopenia

BGA/b-Glucocerebrosidase

 

2-b Protease inhibitor defect

2-b Protease inhibitor defect

2-b Protease inhibitor defect

2-b Protease inhibitor defect

Netherton 's syndrome

AR

Hair shaft defect :

Trichorrhexis invaginata Anaphylactic reactions to food

SPINK5/ LEKTI :

Serine protease Inhibitor

Skin biopsy: absence of LEKTI (immunohistology)

3-b Structural protein defects

3-b Structural protein defects

3-b Structural protein defects

3-b Structural protein defects

K ID syndrome

AD

Deafness

Keratitis

Malformed teeth

GJB2 or GJB6/connexin 26, connexin 30

 

The most recent advances concern the identification of different new genes leading to autosomal-recessive congenital ichthyosis (ARCI) (harlequin fetus, NBIE/LI). The percentage of ichthyoses related to these genes is not yet well known. Epidemiological studies are necessary. More information concerning ARCI genetic defects and their pathomechanisms are essential for providing better treatments in the future, and genetic counseling including prenatal diagnosis.

TGM1  encodes the transglutaminase 1 (TGase1).3-5 TGase 1 expressed in the epidermis is thought to play a key role in the assembly of the cornified cell envelope precursor proteins that will form the cornified cell envelope. TGase 1-defective patients show absent or markedly reduced TGase 1 activity, with a malformed cornified cell envelope, leading to a defect in the intercellular lipid layers in the stratum corneum. The defective stratum corneum barrier function results in an ichthyosis phenotype. Defective TGase 1 has been described in the classical LI phenotype but also in patients with NBIE, and limited genotype/phenotype correlations have been reported.

ALOX12  and  ALOXE3 encode epidermal lipoxygenases. Lipoxygenases form a multigene family of epidermal enzymes, which are preferentially expressed in a differentiation-dependent manner in the epidermis, with a regulatory function in epidermal homeostasis. Their exact functions are still unknown. They may be involved in lipid metabolism in the lamellar granule contents in keratinocytes, and/or in intercellular lipid layers in the epidermis. Patients often are born with collodion membrane, and the LOX mutations lead to a classical phenotype of NBIE/LI phenotype. Further studies are necessary to try to define a real phenotype/genotype correlation, but the phenotypes could be mild, with a frequent spontaneous improvement in the evolution.6-7

ABCA12  encodes a keratinocyte lipid transporter associated with lipid transport in lamellar granules. Defect of ABCA12 function leads to a defective lipid barrier resulting in the NBIE/LI phenotype but also to the harlequin fetus phenotype, in the case of a loss of ABCA12 function.8-9

Ichtyin  encodes a protein that belongs to a new family of proteins of unknown function, localized in the plasma membrane, with homologies to both transporters and G-protein-coupled receptors.10

Clearly, the mutations in any of these new known causative genes are not specific to one disease phenotype alone. A defective formation of the intercellular lipid layers in the stratum corneum secondary to abnormal keratinocyte lipid metabolism or to the transport or the secretion is an essential pathogenic mechanism in inherited ichthyosis.

However, other pathogenic mechanisms not involved in lipid barrier formation can also lead to ichthyosis. In Netherton syndrome, the cutaneous involvement is related to the enhanced activity of a serine protease.

Syndrome of Netherton (SN is characterized by an ichthyosiform erythroderma, an alopecia with a specific hair shaft defect (trichorrexis invaginata, or TI). SPINK5 encoding the protease inhibitor LEKTI is the defective gene in Netherton syndrome. LEKTI is a marker of epithelial differentiation, strongly expressed in the granular and uppermost spinous layers of the epidermis and in differentiated layers of stratified epithelia. The clinical diagnosis of SN can be difficult in the neonate period and even later as TI is not always present, but it's now possible to detect LEKTI in skin biopsies by immunohistochemistry using a specific antibody. If LEKTI is absent when we compare with normal skin as the control, the diagnosis of SN is confirmed.11-12

Pathogenic and physiological mechanisms: The most important advances concerning ichthyoses are the progressive elucidation of their underlying molecular causes, and a great interest of the studies of such rare diseases is to permit a better understanding of the essential physiological mechanisms of cornification and epidermis homeostasis. In fact, the inherited ichthyoses constitute a very large group of different and complex disorders involving primarily the epidermis. In the past, they have been considered as disorders of keratinization, but this term is imprecise as most ichthyoses are not related to keratin disorders. We can observe that the putative defects related to the gene mutations are heterogeneous, involving structural proteins of the corneocyte (eg,. keratins), proteins implicated in the lipid metabolism and in the intercellular lipid lamellae (eg,. transglutaminase 1, lipoxygenase E3, lipoxygenase 12B, ABCA12), or proteins involved in the regulation of intercellular communication or epidermis homeostasis (eg, connexins 26, 30 involved in gap junction, LEKTI). So, today, the term "disorders of cornification" appear better.13 The stratum corneum is the end product of keratinocyte differentiation. It plays a key defensive role (barrier function) to protect against the external environment. It can no more be considered an inert tissue as it is essential in the regulation of epidermal homeostasis.13

Our New Objectives

The complete elucidation of the causative mechanisms and the underlying causes of inherited ichthyoses is a major focus of the ongoing research program, with the identification of new genes involved in the cornification disorders.

However, it is also important to stress that, in contrast with the active molecular research of these last years, the clinical characterization of the inherited ichthyoses and particularly of the autosomal-recessive forms of non-syndromic ichthyosis, have not really been reconsidered. A better clinical characterization of the types and subtypes of these groups of inherited ichthyoses, according to the new scientific knowledge in this field, appears to be essential for the clinicians and for the best management of the patients. Indeed, because of the great genetic heterogeneity of inherited ichthyosis, and even if genetic testing is becoming easier and available for these diseases, it's important to improve rapid diagnostic clinical, histological, and biological procedures. The development of new diagnostic functional tests (immune-detection in the skin, and biological enzyme activity) will speed up diagnosis, in order to orient appropriate molecular research. SN is an example of how helpful diagnostic progress can be with the immune detection of LEKTI in the skin (skin biopsy and immunohistochemistry). Confirmation is now quick and easy when we are confronted with the difficult problem of neonatal erythroderma.

Better genetic counseling, including a prenatal diagnosis if necessary and possible, is also an important objective. Epidemiological studies are necessary. A better research of phenotype-genotype correlation, a better evaluation of clinical characteristics, and clinical prognostic factors are essential. An updated algorithm to speed up clinical (clinical, histological, biological) diagnosis of inherited ichthyosis is under evaluation. A more effective management adapted to each patient and each family is indeed important to define as soon as possible, considering the great heterogeneity of genotypes but also of phenotypes for a same gene.

References

  1. Williams ML, Elias PM. Heterogeneity in autosomal recessive ichthyosis. Clinical and biochemical differentiation of lamellar ichthyosis and nonbullous congenital ichthyosiform erythroderma. Arch Dermatol. 1985;121:477-88.
  2. Akiyama M, Sawamura D, Shimizu H. The clinical spectrum of nonbullous congenital ichthyosiform erythroderma and lamellar ichthyosis. Clin Exp Dermatol. 2003;28:235-40.
  3. Russell LJ, DiGiovanna JJ, Rogers GR, et al. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nat Genet. 1995;9:279-83.
  4. Huber M, Rettler I, Bernasconi K, et al. Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science. 1995;267:525-8.
  5. Petit E, Huber M, Rochat A, et al. Three novel point mutations in the keratinocyte transglutaminase (TGK) gene in lamellar ichthyosis: significance for mutant transcript level, TGK immunodetection and activity. Eur J Hum Genet. 1997;5:218-28.
  6. Jobard F, Lefevre C, Karaduman A, et al. Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. Hum Mol Genet. 2002;11:107-13.
  7. Eckl KM, Krieg P, Küster W, et al. Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. Hum Mutat. 2005;26:351-61.
  8. Hovnanian A. Harlequin ichthyosis unmasked: a defect of lipid transport. J Clin Invest. 2005;115:1708-10.
  9. Akivama M, Sugivama-Nakagiri Y, Sakai K, et al. Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by gene transfer. J Clin Invest. 2005;115:1777-84.
  10. Lefevre C, Bouadjar B, Karaduman A, et al. Mutations in ichthyin a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis. Hum Mol Genet. 2004;13:2473-82.
  11. Chavanas S, Bodemer C, Rochat A, et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2000;25:141-2.
  12. Bitoun E, Micheloni A, Lamant L, et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution, and defective expression in Netherton syndrome. Hum Mol Genet. 2003;12:2417-30.
  13. Elias PM, Williams ML. Ichthyosis: Where we have been disorders of cornification: Where we are going. Curr Probl Dermatol. 2000;12:170-6.

 

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