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Ichthyoses: Differential diagnosis and molecular genetics

European Journal of Dermatology. Volume 16, Numéro 4, 349-59, July-August 2006, Review article

Summary

Auteur(s) : Vinzenz Oji, Heiko Traupe , Department of Dermatology, University Hospital, Von-Esmarch-Str. 58, 48149 Münster, Germany Fax: +49 (0) 251 83 56 945.

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ARTICLE

Auteur(s) : Vinzenz Oji, Heiko Traupe

Department of Dermatology, University Hospital, Von-Esmarch-Str. 58, 48149 Münster, Germany Fax: +49 (0) 251 83 56 945

accepté le 11 Janvier 2006

Ichthyoses form a clinically and etiologically heterogeneous group of cornification disorders characterized by a generalized scaling of the skin. The large group of congenital ichthyoses (CI), which at birth typically present with collodion membrane or ichthyosiform erythroderma, encompasses an apparently confusing number of very rare diseases and often poses a diagnostic challenge for the clinician confronted with ichthyotic symptoms. First of all, it is necessary to distinguish congenital ichthyosis from common ichthyosis vulgaris (IV) and X-linked recessive ichthyosis (XLRI), which both manifest after birth. It is then recommended to look for outstanding associated non-cutaneous symptoms, which may give a useful diagnostic hint for recognising a special syndrome with associated vulgar or congenital ichthyosis [1]. The precise patient and family history, the dermatological features, coupled with the histological and ultrastructural analysis of the skin and in some cases additional biochemical analyses, will help to establish the correct diagnosis necessary for prognosis, therapy and genetic counselling. If possible diagnosis should be confirmed by genetic analysis/mutation screening.The advances in molecular biology have provided a battery of new diagnostic means and are beginning to allow a refined classification of ichthyoses and other cornification disorders such as erythrokeratoderma and palmoplantar keratoderma [2]. This review describes their differential diagnosis and molecular pathology according to the above mentioned clinical criteria. Isolated ichthyoses are summarized in table 1, ichthyotic syndromes in table 2.

Vulgar ichthyoses

Ichthyosis vulgaris (IV) versus X-linked recessive ichthyosis (XLRI)

( Table 1 )( Table 2 )Clinically, it is often difficult to make a clear distinction between these two common ichthyoses (prevalence 1:250-1,000 and 1:2,000-1:6,000, respectively), even though they show a different mode of inheritance. Autosomal dominant ichthyosis vulgaris is characterised by follicular keratosis and light grey scales, which normally spare the flexures. Accentuated palmoplantar markings, the hallmark of ichthyosis vulgaris, are not always evident [3]. The clinical severity of ichthyosis vulgaris correlates with the ultrastructural reduction of keratohyalin granules, which reflects a defective epidermal synthesis of filaggrin [4]. Filaggrin aggregates keratin intermediate filaments in the lower stratum corneum and is subsequently proteolysed to form free amino acids critical as water-binding compounds of the stratum corneum, such as urocanic or pyrrolidone carboxylic acid. Absence of the granular layer observed by light microscopy is a prominent feature of ichthyosis vulgaris [5]. However, this varies among individuals and is not reliable [6]. In our experience, there can be intra-individual variation of the granular layer in ichthyosis vulgaris. Therefore, to fully appreciate this histologic feature, a biopsy should be taken from a site of maximal scaling.

In contrast, X-linked recessive ichthyosis caused by mutations in the steroid sulfatase gene (STS) can be unequivocally diagnosed by steroid sulfatase (~ Arylsulfatase C) testing [7]. The disorder sometimes presents with fine peeling of the entire integument at the age of 1-3 weeks and shows fine scaling in early life. Later on, affected individuals typically develop polygonal dark scales ( (figure 1A) ). Flexures are also involved, but often to a minimal extent mimicking ichthyosis vulgaris. Lipoproteinelectrophoresis showing an increased mobility of beta-lipoprotein is a convenient way to screen for steroid sulfatase deficiency [8]( (figure 1B) ). The pathogenesis of XLRI has been a subject of considerable research; the development of ichthyosis is usually attributed to the perturbed epidermal cholesterol sulfate cycle and the accumulation of cholesterol sulfate. In particular, increased amounts of cholesterol sulphate inhibit epidermal serine proteases such as kallikreins [9]. This results in retained corneodesmosomes and consequently decreased desquamation of corneocytes.

In ichthyosis vulgaris as well as in X-linked recessive ichthyosis the clinician should ask for non-cutaneous symptoms. Ichthyosis vulgaris is often associated with atopic diathesis. XLRI possibly includes birth complications, cryptorchidism and corneal opacities [1, 3].
Table 1 The term isolated ichthyosis refers to ichthyoses which are not part of a disease syndrome. They are clinically distinguished in two subclasses: common ichthyoses with an age of onset after birth (vulgar ichthyoses) and rare ichthyoses presenting at birth (congenital ichthyoses)

Disease	Mode of inheritance	Gene/Locus	OMIM	Molecular pathology
Isolated vulgar ichthyoses
Ichthyosis vulgaris (IV)	Autosomal dominant	FGL 1q21-22	146700	- Genetical heterogeneous / polygeneous - Abnormalities of profilaggrin expression
Recessive X-linked ichthyosis (RXLI)	X-linked recessive	STS Xp22.3	308100	- Absence of steroid sulfatase activity - Accumulation of cholesterol sulphate - Inhibition of tryptic enzymes
Isolated congenital ichthyoses
Lamellar ichthyosis / non-bullous congenital ichthyosiform erythroderma (LI/NCIE) - LI phenotype - NCIE phenotype - intermediate phenotype	Autosomal Recessive Congenital Ichthyoses (ARCI) (non-syndromic type)	LI type 1-6: 1. TGM1 14 q11 2. ABCA12 2q34 3. 19p12-q12 4. 19p13 5. ALOXE3 ALOX12B 17p13 6. ichthyin 5q33	190195 242300 607800 601277 604777 604781 607206 603741 606545 609383	(1) transglutaminase-1 deficiency, impaired cross-linking of proteins and lipids to the cornified cell envelope (2) disrupted ATP-binding cassette of the ABC membrane protein, altered lipid trafficking of lamellar bodies (5) loss of function of the lipoxygenases eLOX or 12R-LOX, disrupted trans-formation process of arachidonic acid (6) disruption of ichthyin, which is a transmembrane protein of unknown function so far
Self-healing collodion baby (SHCB)	TGM1 14q11	242300	- Particular missense mutations in tranglutaminase-1 rendering the protein susceptible to water pressure
Bathing suit ichthyosis (BSI)	?		Unknown
Harlequin ichthyosis (HI)	ABCA12 2q34	607800 242500	- Loss of function of the ABC transporter protein A12 and disrupted function of the lamellar bodies
Autos. dominant lamellar ichthyosis (ADLI)	Autosomal dominant	?	146750	Unknown
Bullous ichthyosiform erythroderma (BIE)	Autosomal dominant	KRT1 KRT10 17q21-q22 & 12q13	139350 148080 113800	- Dominant mutations in keratin 1 or keratin 10 leading to a fragmenting and perinuclear clumping of tonofilaments in the stratum spinosum
Ichthyosis bullosa of Siemens (IBS)	KRT2A (~KRT2E) 12q11-q13	600194 146800	- Dominant mutations in keratin 2e, leading to a clumping of tonofilaments restricted to the upper stratum spinosum and stratum granulosum
Ichthyosis hystrix Curth Macklin (IHCM)	KRT1 12q13	139350 146590	- Keratin disorder due to a specific mutation in the variable tail domain V2 of keratin 1
Peeling skin syndrome (PSS)	Autosomal recessive	TGM5 15q15	270300	- Homozygous missense mutations in transglutaminase-5 leading to a complete loss of enzyme activity in acral PSS

Table 2 Syndromes with associated ichthyosis. These diseases are clinically distinguished by the age of onset of the ichthyosis. Affected individuals may show dermatological features similar to vulgar ichthyoses or may be born with collodion membrane or ichthyosiform erythroderma, as is the case with congenital ichthyoses

Disease	Mode of inheritance	Gene / Locus	OMIM	Molecular pathology
Syndromes with vulgar ichthyosis
Refsum disease (HMSN4)	autosomal recessive	PHYH 10pter-p11.2 PEX7 6q22-q24	266500	- Special variant of peroxisomal disorder - Disrupted oxidation of phytanic acid - Accumulation of phytanic acid in tissues
Multiple sulfatase deficiency (MSD)	SUMF1 3p26	607939 272200	- Lysosomal storage disorder - Deficient posttranslational modification of sulfatases including the steroid sulfatase
Syndromes with congenital ichthyosis
Dorfman Chanarin syndrome (DCS)	autosomal recessive congenital ichthyosis (ARCI (syndromic type)	CGI58 3p21	604780 275630	- Multisystem triglyceride storage disease - Impaired function of a novel esterase/ lipase/thioesterase, which is responsible for the long-chain fatty acid oxidation
Gaucher syndrome type 2 (GD2)	GBA 1q21	606463 230900	- Lysosomal storage disease due to a loss of the glucocerebrosidase activity - Accumulation of glucocerebrosides in peripheral leukocytes and body tissues including the central nervous system
Sjögren Larsson syndrome (SLS)	ALDH3A2 17p11.2	270200	- Impaired oxidation of aliphatic aldehydes due to a defect of the microsomal fatty aldehyde dehydrogenase - Abnormal metabolism of lipids in the skin and phospho- or sphingolipids in the brain
Comèl-Netherton syndrome (NTS)	SPINK5 (5q32)	256500	- Deficiency of the serine protease inhibitor LEKTI, which is normally expressed in the upper epidermal layer controlling proteases involved in desquamation and inflammation
Trichothio-dystrophy (TTD) - Tay syndrome (IBIDS / PIBIDS)	ERCC2 / XPD 19q13.2-q13.3 ERCC3 / XPB 2q21 TTD-A	278730 126340 601675 133510 -	- Impaired DNA transcription and repair - Allelic variants cause Xeroderma Pigmentosa and Cockayne syndrome - The molecular cause of TTD without photosensitivity (IBIDS) is unknown
Ichthyosis prematurity syndrome (IPS)	9q33-34	608649	unknown
Conradi-Hünermann-Happle syndrome (CDPX2)	X-linked dominant	EBP Xp11.23-p11.22	300205 302960	- Impaired cholesterol synthesis due to mutations in the sterol isomerase (EBP), which is the key enzyme in the final step of cholesterol biosynthesis - Interference with “sonic hedgehog”
CHILD syndrome	X-linked dominant	NSDHL Xq28	300275 308050	- Blockade of cholesterol biosynthesis pathway prior to the sterol isomerase - Defect of the embryogenesis of the bilateral body symmetry
IFAP syndrome	(X-linked recessive)	unknown	308205	- Unknown - Genetic heterogeneity or a different mode of inheritance is possible

Syndromes with associated vulgar ichthyosis

Some rare syndromes are associated with “vulgar” ichthyoses. This group comprises multiple sulfatase deficiency (MSD) and Refsum disease (RD).

Clinical symptoms of Refsum disease, also referred to as hereditary motor and sensory neuropathy type 4 (HMSN4), include night blindness (retinitis pigmentosa), anosmia, progressive deafness, peripheral neuropathy and cerebellar ataxia. The age of onset varies from early childhood to the age of ~50 [10]. Many patients develop ichthyotic skin reminiscent of ichthyosis vulgaris. The disease is caused by mutations in PHYH, the gene encoding phytanoyl-CoA hydroxylase (PhyH) [11]. The impaired function of PhyH results in a pathologic plasma and tissue accumulation of phytanic acid. Early diagnosis and treatment with a diet low in phytanic acid can prevent the fatal course of the disease [12]. The oxidation of phytanic acid by PhyH is dependent on the Pex7p protein, which is an important peroxisomal receptor. Mutations in the PEX7 gene cause the severe peroxisome biogenesis disorder rhizomelic chondrodysplasia punctata type 1 (RCDP1), which may also be accompanied by mild ichthyosis [13]. Interestingly, special variants of PEX7 can also cause Refsum disease [14].

Multiple sulfatase deficiency is a rare neuropediatric disorder, which combines the enzyme deficiency and clinical features of diseases such as metachromatic leukodystrophy, mucopolysaccharidoses and steroid sulfatase deficiency. Affected infants suffer from progressive psychomotor deterioration and have a very poor prognosis. This “lysosomal storage disorder” is caused by recessive mutations in SUMF1, which encodes the FGly generating enzyme (FGE) [15]. This enzyme catalyses the posttranslational formation of FGly residues, which are functionally important catalytic residues in the active site of eukaryotic sulfatases. Hence, a lack of FGE leads to an impaired function of all sulfatases including steroid sulfatase, the defective enzyme in XLRI. Multiple sulfatase deficiency patients show an ichthyosis, which is similar to but usually milder than in XLRI. Therefore, ichthyosis in a child with unexplained neurological symptoms should prompt measurement of steroid sulfatase [16]. There are other syndromes apart from multiple sulfatase deficiency, which are associated with XLRI and are due to a contiguous gene deletion, affecting neighbouring genes of the steroid sulfatase gene [17]. This mechanism can be observed in Kallman syndrome, hypertropic pyloric stenosis, unilateral renal aplasia, mental retardation or hypergonadotropic hypogonadism [1].

Isolated congenital ichthyoses

Isolated congenital ichthyosis encompasses a group of mostly monogenic disorders presenting at birth with generalized hyperkeratosis and scaling (e.g. collodion membrane), often with erythroderma. Neonates with bullous types of congenital ichthyosis typically show skin erosions and blistering. Associated clinical symptoms are neonatal dehydration, skin infections, ectropion, eclabium, hypohidrosis or severe heat intolerance.

Lamellar ichthyosis (LI)/non-bullous congenital ichthyosiform erythroderma (NCIE)

This subgroup of different types of non-syndromic autosomal recessive congenital ichthyoses (ARCI) is characterised by non-bullous hyperkeratosis. The more severe phenotype, lamellar ichthyosis (LI) has an estimated prevalence of 1:200,000-300,000. Most patients (~90%) are born encased in a tight shiny covering, described as collodion membrane, and often show erythroderma. During the first weeks of life, the membrane is gradually replaced, and patients develop large, dark or plate-like scales ( (figure 1E) ), sometimes with marked palmoplantar hyperkeratosis. In contrast, individuals with non-bullous congenital ichthyosiform erythroderma (NCIE) show a more pronounced erythroderma with fine, white scaling [18]( (figure 1C) ). Non-erythrodermic, non-lamellar ARCI is regarded as a very mild intermediate phenotype within the spectrum of lamellar ichthyosis (LI) situated at one end of the pole and non-bullous congenital ichthyosiform erythroderma (NCIE) at the other [19, 20].

To date, six genes for lamellar ichthyosis/non-bullous congenital ichthyosiform erythroderma (LI/NCIE) (type1-6) [19, 21-23] have been localised and five of them identified [24-27] (table 1). In about 35-40% LI/NCIE is caused by homozygous or compound heterozygous mutations in TGM1 (LI/NCIE type 1), which lead to a deficiency of keratinocyte transglutaminase. Transglutaminases are Ca²⁺-dependent enzymes involved in the assembly of the cornified cell envelope. This resilient sheath of ε-(γ-glutamyl)lysine cross-linked proteins is deposited subjacent to the plasma membrane in terminally differentiating keratinocytes. The covalent γ-amide bonds between various proteins or peptides are formed by transglutaminase-1, -3 and -5. An important specific function of transglutaminase-1 is the cross-linking of ω-hydroxyceramides to the cornified cell envelope [28]( (figure 2) ). The LI/NCIE locus on chromosome 17p13, which is more often associated with the NCIE phenotype, revealed missense mutations or deletions in ALOXE3 or ALOX12B [26]. These genes encode epidermal lipoxygenase-3 (eLOX3) and 12R-lipoxygenase (12R-LOX). Lipoxygenases are iron-containing dioxygenases, which metabolise essential fatty acids, phospholipids or triglycerids. In the epidermis, eLOX3 and 12R-LOX participate in the same metabolic pathway, which converts arachidonic acid into specific epoxyalcohol products. Loss of function in one of these enzymes probably impairs the epidermal lipid formation [29, 30]. Lefèvre et al. (2004) reported about a new gene on chromosome 5q33 (LI/NCIE type 6), mutations of which cause a NCIE-like phenotype, which was always accompanied by palmoplantar keratoderma [27]. 60% of the patients were born with a collodion membrane. They showed that the causative gene ichthyin encodes a putative transmembrane protein and speculated that it could be a receptor for products of the epoxyalcohol/lipoxygenase pathway [27, 29]. Patients with IL/NCIE type 2 (2q34) were all born with a collodion membrane and presented a generalised pure lamellar ichthyosis with palmoplantar keratoderma [21]. This phenotype was associated with missense mutations in the ABCA12 gene [25], the same gene, in which large intragenic deletions and frameshift deletions cause Harlequin ichthyosis [31]. The exact molecular cause of LI/NCIE type 3 and 4 remains to be established. Attempts to refine the classification of LI and NCIE phenotypes by the use of clinical, biochemical and ultrastructural observations have so far failed to yield a consistent scheme. This difficulty is illustrated by the fact that the same TGM1 mutation can give rise to either LI or NCIE [32].

The distinct phenotype self-healing collodion baby (SHCB) can be due to a particular mutation in TGM1, which leads to an impaired transglutaminase-1 function under intrauterine water pressure [33]. Approximately 10% of all collodion babies heal completely within the first weeks of life (( figure 1 )F and 1G). The molecular basis of bathing suit ichthyosis (BSI), which is a variant of lamellar ichthyosis sparing the extremities and the face, is unknown so far.

Harlequin ichthyosis (HI)

The newborn who suffers from this most severe ichthyosis is encased in a thick collodion membrane, showing cracking with deep fissures, pronounced ectropion/eclabium and often impaired mobility of the thorax and limbs. The prognosis is poor because of secondary complications, but some patients can be rescued with an early treatment of retinoids and intensive care ( (figure 1H) ). Lawlor (1988) suggested that Harlequin ichthyosis may be a severe form of lamellar ichthyosis/non-bullous congenital ichthyosiform erythroderma [34] and was proven right 17 years later, when it was demonstrated, that at the one hand missense mutations in ABCA12 can cause classic lamellar ichthyosis [25], whereas deletions in this gene predicting a severely truncated protein are the molecular cause of Harlequin ichthyosis [31]. The ATP-binding cassette (ABC) transporter family encompasses a variety of membrane proteins involved in the energy-dependent transport across membranes. In the epidermis, ABCA12 could have an important function for the lamellar granules, which through exocytosis traffic lipids, proteases, etc. across the apical keratinocyte membrane. The ultrastructural key feature of HI is the abnormal formation of lamellar granules [35].

Autosomal dominant lamellar ichthyosis (ADLI)

Autosomal dominant lamellar ichthyosis is characterised by a generalised dark-grey scaling with palmoplantar keratoderma [36]. Its genetic cause is not known so far. This disorder appears to be genetically and clinically heterogeneous and of variable penetrance. Ultrastructurally a prominent transforming zone between the stratum granulosum and corneum can be observed [37]. An important differential diagnosis is loricrin keratoderma (see below).

Bullous ichthyosiform erythroderma (BIE) and ichthyosis bullosa of Siemens (IBS)

The term epidermolytic hyperkeratosis derives from the characteristic light microscopic observation intracellular vacuolisation, clumping of tonofilaments and formation of small intraepidermal blisters. It is typically present in bullous ichthyosiform erythroderma of Brocq (BIE), which is also referred to in the American literature as epidermolytic hyperkeratosis (EHK), in ichthyosis bullosa of Siemens (IBS) and in palmoplantar keratoderma of Voerner (EPPK).

Keratins comprise a large family of > 20 proteins, which are expressed in pairs of acidic (type I) and basic (type II) keratins (encoded on chromosome 17q12-21 and 12q11-13, respectively). Keratin monomers form obligate heterodimers, which assemble into keratin intermediate filaments building a cytoskeleton for the structural stability and flexibility of epidermal cells. In the skin, basal keratinocytes predominantly express keratin 5 and 14, while suprabasal cells switch to the expression of keratin 1 and 10. Cells of the granular layer also synthesize keratin 2e.

Like other keratinopathies, bullous ichthyosiform erythroderma (BIE) is inherited by an autosomal dominant trait. Individuals affected at birth show a generalised erythroderma, often with widespread blistering or erosions. The hyperkeratosis begins later and persists throughout the rest of life ( (figure 1I) ). The disorder is caused by heterozygous mutations of KRT1 (keratin 1) and KRT10 (keratin 10) [38, 39]. More than half of all cases are due to a de novo mutation and occur sporadically. Patients with bullous ichthyosiform erythroderma and KRT1 mutations often develop palmoplantar keratoderma, because keratin 1 is the main expression partner of keratin 9 in palmoplantar skin. Linear epidermolytic epidermal nevi (along the lines of Blaschko) indicate a somatic and maybe gonadal mosaicism, which can result in generalised full-blown BIE in the offspring generation [40]. The diagnostic ultra structural finding of BIE is the cytoplasmatic clumping of tonofilaments in the suprabasal or spinous layer [41].

Clinically, ichthyosis bullosa of Siemens (IBS) has a milder phenotype than bullous ichthyosiform erythroderma and can be distinguished by the lack of erythroderma and by a characteristic “moulting” of the upper epidermal layers ( (figure 1J) ). Lichenified hyperkeratosis develops with a predilection to flexures, over joints and on dorsa of hands and feet [42]. The disorder is caused by heterozygous mutations in the gene of keratin 2e [43, 44]. Light microscopy reveals a superficial acanthokeratolysis in the granular layer (versus spinous layer in BIE), which correlates with the distinct expression pattern of keratin 2e.

Ichthyosis hystrix Curth Macklin (IHCM)

“Ichthyosis hystrix” is a descriptive name for cornification disorders with massive and spiky hyperkeratosis. The prototype is ichthyosis hystrix Curth Macklin, which is characterised by extensive keratoderma and verrucous hyperkeratosis over joints and flexures [45]. The autosomal dominant disorder sometimes resembles bullous ichthyosiform erythroderma, but there is no clinical or histological evidence for blister formation or epidermolysis. The prominent ultrastructural observations in ichthyosis hystrix Curth Macklin are abnormal cytoplasmic aggregates of tonofilaments, perinuclear vacuolisation and binucleated cells. The IHCM specific pathology is due to particular heterozygous mutation in KRT1 [46].

Peeling skin syndrome (PSS)

The peeling skin syndrome is characterized by a spontaneous, lifelong peeling of the stratum corneum without bleeding or pain [47]. Ultrastructural analyses reveal an intracellular splitting within the stratum corneum. Peeling skin syndrome type A is the non-inflammatory variant presenting at birth or during childhood; peeling skin syndrome type B seems to be identical with Netherton syndrome [48]. Another acral localised variant of PSS has been described [49]. A recent study identified a homozygous missense mutation in the gene of transglutaminase-5 (TGM5) in two unrelated families with acral peeling skin syndrome [50].

Syndromes with congenital ichthyoses

Dorfman Chanarin Syndrome (DCS)

The multisystem triglyceride storage disease with impaired long-chain fatty acid oxidation is a rare form of syndromic non-bullous congenital ichthyosiform erythroderma [51] and is caused by recessive mutations in the CGI58 gene [52]. At birth individuals suffering from Dorfman Chanarin Syndrome present with generalised white scaling and a variable degree of erythema. The skin shows a characteristic ultrastructure [53]. The widespread non-lysosomal tissue deposition of neutral lipids results in a variable expression of associated symptoms such as cataract, hepatosplenomegaly, neurosensorial deafness, myopathy or developmental delay. Numerous lipid-containing vacuoles in circulating leukocytes are diagnostic for the disorder. Prognosis depends on the course of the liver disease, which may be positively influenced by a diet of medium-chain triglyceride [54].

Gaucher syndrome type 2 (GD2)

Gaucher disease refers to a cluster of disorders resulting from recessive mutations in the GBA gene encoding glucocerebrosidase, an enzyme that normally cleaves the glucose residue from ceramides ( (figure 2) ). As a result, glucocerebrosides accumulate in the phagocytic cells or central nervous system. Three clinical subtypes have been distinguished. Type 2, the infantile cerebral type, is characterised by an almost complete loss of glucocerebrosidase activity, hepatosplenomegaly and dominating progressive neurologic signs such as opisthotonus, choking spell and dysphagia, leading to death usually before the age of 1 year [55]. Some but not all patients are born as collodion babies. Therefore, Gaucher syndrome type 2 is a differential diagnosis for other types of congenital ichthyosis [56]. Diagnosis can be made by measurement of glucocerebrosidase activity in peripheral blood leukocytes or in extracts of cultured skin fibroblasts.

Sjögren Larsson syndrome (SLS)

Sjögren Larsson syndrome is a recessive neurocutaneous disorder caused by a deficiency of the mircrosomal enzyme fatty aldehyde dehydrogenase (FALDH) [57], which for example is involved in the leukotriene B₄ (LTB₄) metabolism. The diagnosis of SLS should be especially considered in preterm babies with congenital ichthyosis [58]. Sjögren Larsson syndrome skin is characterised by a remarkable, cobblestone-like lichenification ( (figure 1L) ). Severe disabling pruritus, crystalline deposits in the retina appearing as glistening white dots and photophobia are very characteristic non-cutaneous symptoms. During infancy and childhood SLS patients develop severe body spasticity, leading to contractures and, in most patients, to wheelchair dependency. Non-progressive, mild to moderate mental retardation is a coexisting neurological feature. The pathologic level of free fatty alcohols in cultured fibroblasts, the direct testing of the FALDH activity, or the abnormal presence of LTB₄ metabolites in urine [58], can provide a biochemical screening or confirmation of the clinical diagnosis, prior to molecular mutation analysis of the FALDH gene.

Netherton syndrome (NTS)

This rare autosomal recessive ichthyotic syndrome is characterised by the triad of congenital ichthyosiform erythroderma, hair shaft anomalies and severe atopic diathesis with high IgE blood levels and eosinophilia. Normally congenital ichthyosiform erythroderma ( (figure 1M) ) gradually evolves into the milder ichthyosis linearis circumflexa, which typically shows polycyclic migrating plaques with double edged scales. Trichorrhexis invaginata is the pathognomonic microscopic hair shaft anomaly of Netherton syndrome ( (figure 1N) ). Many NTS patients suffer from life threatening neonatal dehydration, failure to thrive and recurrent skin infections often caused by staphylococcus aureus [59]. This disorder is caused by recessive mutations in the SPINK5 gene, which encodes the novel multi-domain serine protease inhibitor LEKTI [60, 61]. Full-length LEKTI is proteolytically processed in the upper epidermal layer, forming small biological active peptides, which inhibit a variety of serine proteases such as stratum corneum trypsin or chymotrypsin enzyme (SCTE/SCCE) or mast cell tryptase. The ichthyotic and inflammatory skin phenotype, which is associated with an extremely impaired epidermal barrier, is explained by the lack of LEKTI, which consequently leads to hyperactivity of the proteases involved in the desquamation process or inflammatory response (kallikreins). Thus, from a pathophysiologic point of view, Netherton syndrome represents the opposite pole of X-linked recessive ichthyosis, which is characterised by a reduced serine protease activity in the epidermis [9]. The lack of LEKTI antigen in the epidermis provides a strong immunochemical evidence for the NTS diagnosis (( figure 1O and 1P) )[62].

Ichthyosis prematurity syndrome (IPS)

Ichthyosis prematurity syndrome is often reported in the Scandinavian population, but can also be found in German patients (our experience). Pregnancies with an affected foetus are complicated by polyhydramnion; delivery usually takes place in the 30th-32nd gestational week. Neonates may suffer from transient asphyxia. The ichthyosis often improves within a few weeks. The skin shows a characteristic ultrastructure, which has lead to the designation ichthyosis congenita type 4. A novel locus for the ichthyosis prematurity syndrome was assigned for chromosome 9q33-34 [63].

Conradi-Hünermann-Happle syndrome (CDPX2)

X-linked dominant chondrodysplasia punctata type 2 (CDPX2), also known as Conradi-Hünermann-Happle syndrome, is lethal in the majority of male embryos and consequently only seen in female patients [64, 65]. Due to the individual differences in X-inactivation, expression of the disease is rather variable even within families. Females affected at birth often present with severe ichthyosiform erythroderma, which in infancy later evolves into striated hyperkeratosis following the lines of Blaschko (ichthyosis linearis). After infancy patients mainly suffer from scaring alopecia, cataracts and the skeletal dysplasia, which leads to asymmetric shortening of the long bones or severe kyphoscoliosis, necessitating early orthopaedic interventions. Some individuals only show minor symptoms such as localised hypo-/hyperpigmentations or short stature. Follicular atrophoderma, i.e. large skin pores, or sectorial cataracts are pathognomonic for Conradi-Hünermann-Happle syndrome. Biochemical analyses via gas chromatography-mass spectrometry reveal increased plasma level of 8-dehydrocholesterol and 8(9)-cholesterol, which is due to a block of a key enzyme in the sterol metabolism, namely the 8-7 sterol isomerase [66]. This enzyme is encoded by the EBP gene, which shows heterozygous mutations in CDPX2 patients. Direct sequencing of EBP should confirm the diagnosis of CDPX2. The mechanism behind the intrauterine loss of affected males and the dermatoskeletal dysplasia is unclear and may include the accumulation of toxic sterol intermediates and the deficiency of products distal in the cholesterol biosynthesis pathway.

CHILD syndrome

CHILD is an acronym for congenital hemidysplasia with ichthyosiform nevus and limb defects [67]. This X-linked dominant dysplasia is also determined by the phenomenon of X-chromosome inactivation. Like CDPX2, it is lethal in males and therefore almost exclusively observed in females. The syndrome is caused by mutations in the NSDHL gene encoding the 3β hydroxysteroid dehydrogenase also known as C3 sterol dehydrogenase [68]. This enzyme of the cholesterol biosynthesis pathway is located prior to the 8-7 sterol isomerase, the enzyme impaired in Conradi-Hünermann-Happle syndrome (CDPX2). The most striking feature in the CHILD syndrome is the inflammatory nevus, which has a highly characteristic ultrastructure and normally shows a unique lateralisation with strict midline demarcation. The ipsilateral hypoplasia of the body may be represented by a shortening or even complete absence of a limb.

Trichothiodystrophy (TTD)

Trichothiodystrophy refers to a heterogeneous group of autosomal recessive disorders that share the distinctive features of extremely brittle hair and abnormally low sulfur content of the hair shaft (decrease of cysteine). Trichochisis and alternating light and dark banding by polarizing microscopy are typical findings, but they may occasionally occur in patients without this disorder as well [69]. In particular, zinc deficiency can produce similar clinical hair alterations [70]. At least two TTD subtypes are associated with congenital ichthyosis: The acronym IBIDS describes the distinct “Tay syndrome” and refers to its clinical findings ichthyosis (e.g. collodion membrane), brittle hair, intellectual impairment, decreased fertility and short stature. Other features are microcephaly, dysplasia of nails, failure to thrive, “progeria”-like symptoms, cataracts and photosensitivity (~PIBIDS) [71]. Half of all trichothiodystrophy patients show an abnormal nucleotide excision repair (NER) of UV-damaged DNA, which is caused by recessive mutations in the XPD gene (in about 95%), in the XPB gene or in the predicted gene “TTD-A”. It is believed that most individuals with IBIDS/PIBIDS do not have an increased risk of skin cancers [69], but rare cases with an overlapping phenotype of trichothiodystrophy and Xeroderma pigmentosum (XP) with skin cancers have been described [72, 73]. Therefore, sun protective measures should be recommended for TTD patients.

IFAP syndrome

The acronym IFAP stands for ichthyosis follicularis, atrichia and photophobia [74]. The congenital and universal atrichia is the most striking clinical feature (( figure 1 )K). The follicular keratosis often improves during the first year of life and should be distinguished from other diseases such as keratosis follicularis spinulosa decalvans of Siemens or simply ichthyosis vulgaris. The cause of the photophobia is unclear and may be related to follicular keratosis within the eye lids. Some patients also suffer from recurrent respiratory infections or progressive deteriorating neurologic symptoms such as generalised seizures and cerebellar symptoms. The complete IFAP phenotype seems to be only observed in male patients. It is therefore thought to be of X-linked recessive inheritance. Female carriers may present with linear “lesions of Blaschko” showing circumscribed hairless or ichthyotic skin areas [75]. A different mode of inheritance and genetic heterogeneity was considered by Cambiaghi et al. (2002) [76].

Related types of cornification disorders

This group refers to erythrokeratoderma and palmoplantar keratoderma, which have been historically separated from ichthyoses. The following entities may have a considerable clinical or etiological overlap with ichthyoses.

Erythrokeratodermia variabilis of Mendel Da Costa (EKV) (OMIM 133200) is due to recessive mutations in the genes of connexin 31 or 30.3 [77]. Connexins are essential components of the intercellular gap junction communication, which is crucial for tissue homeostasis, growth control, development and synchronized response of cells to stimuli. EKV is characterised by transient, figurate erythemas, which can be easily provoked by external factors, and hyperkeratosis with developing pachydermia. Patients also suffer from palmoplantar keratosis and burning sensations of involved extremities. There is no characteristic ultrastructure in this disorder. The so called keratitis ichthyosis deafness (KID) syndrome (OMIM 148210) is a rare ectodermal dysplasia, which is characterised by corneal epithelial defects, sometimes leading to blindness, and a development of follicular hyperkeratosis with circumscribed, erythematous plaques of thickened skin. The hearing loss is not always bilateral, nor always complete. In contrast to erythrokeratodermia variabilis of Mendel Da Costa, the dominant inherited KID syndrome is caused by heterozygous mutations in CX-26, the gene of connexin 26 [78]. The majority of all KID syndrome cases seem to occur sporadically. The specific mutation D66H of CX-26 can also cause congenital deafness with mutilating keratoderma (Vohwinkel syndrome) (OMIM 124500) [79], which demonstrates the multiplicity of phenotypes in connexin disorders. The variant form of Vohwinkel syndrome, referred to as loricrin keratoderma (OMIM 604117), is caused by mutations in the gene for loricrin and, in contrast to erythrokeratodermas, shows a characteristic ultrastructure with compact hyperkeratosis, round retained nuclei and hypergranulosis [80]. Affected individuals may show congenital ichthyosis prior to the development of palmoplantor keratoderma with pseudoanihum, illustrating that keratoderma has to be added to the differential diagnosis of collodion babies and ichthyosis.

Conclusion

Ichthyoses form an extremely heterogeneous group of inherited diseases; most of them are rare and therefore difficult to diagnose. From the clinical point of view it is useful to distinguish between vulgar or congenital and isolated or syndromic ichthyoses. Histological features such as epidermolytic hyperkeratosis (BIE, IBS), ultrastructural findings such as cholesterol clefts, lipid vacuoles, malformed cornified cell envelope (LI/NCIE) and abnormal lamellar granules (HI), or biochemical results such as the lack of transglutaminase activity (LI/NCIE) or of LEKTI (NTS) expression, may be regarded as effective diagnostic or screening tools. Other diagnostic procedures include blood/plasma analyses for steroid sulfatase activity (XLRI, MSD), phytanic acid (HMSN4), lipid vacuoles of leukocytes (DCS), glucocerebrosidase activity (GD2), 8-dehydrocholesterol and 8(9)-cholestenol (CDPX2) or analyses for the aldehyde dehydrogenase (FALDH) activity in cultured fibroblasts (SLS) or for the amino acid content of the hair (TTD). Most of these procedures have to be carried out in specialised centres. The transglutaminase activity test developed at our Centre in Münster ( (figure 1D) ) is performed with unfixed cryosections, which have to be sent on dry ice.

Further information concerning diagnostic as well as therapeutic questions can be downloaded from the “Network for Ichthyosis and Related Cornification Disorders” NIRK (www.netzwerk-ichthyose.de) or can be given via E-mail from the authors. NIRK is closely linked to the German self support group “Selbsthilfe Ichthyose e.V.” (www.ichthyose.de) and is open to international collaborators. Further research is necessary for a better understanding of the pathogenesis of all cornification disorders, which will enable improved diagnostics and treatment of these diseases. Very recently, two homozygous or compound heterozygous nonsense mutations have been identified in the filaggrin (FGL) in ichthyosis vulgaris patients [82]. These mutations are also associated with atopic dermatitis [83]

Acknowledgements

We thank Mrs. Bückmann, Mr. Wissel and Mr. Thomas for the help with the photographs, Mrs. Gamble-Brodte for the revision of the manuscript, and we would like to dedicate this review to all our patients and their families. Special thanks to Stefan and Melody. Our work is supported by the Deutsche Forschungsgemeinschaft (Tr 228/6-2) and by the Bundesministerium für Bildung und Forschung as part of the Network for rare diseases NIRK (GFGM01143901)

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