Autosomal-dominant lamellar ichthyosis: Ultrastructural characteristics of a new type of congenital ichthyosis

Summary Recently, autosomal-dominant lamellar ichthyosis (ADLI) has been shown to be a new genetic trait with clinical and histologic features similar to those of autosomal-recessive lamellar ichthyosis. In two patients affected with ADLI, the malpighian keratinocytes showed ultrastructural signs of increased cellular metabolism. The tonofilaments and keratohyaline granules were regular in structure and number. However, as a distinctive ultrastructural feature, a prominent transforming zone was found between the granular and horny layers. Moreover, a normal keratin pattern and only a limited number of lipid inclusions were observed in the stratum corneum. Thus, ADLI can be distinguished from the autosomal-recessive forms of lamellar ichthyosis, permitting a correct diagnosis when genetic counselling has to be given in sporadic cases.     

Ichthyosis congenita type III

Summary We describe one type of the heterogeneous ichthyosis congenita group, inherited autosomal-recessively, noting its clinical and ultrastructural features based on the findings in a female patient, aged 30 at the time of first clinical and ultrastructural investigation, and supplemented with those of eight further patients, aged 2 to 22 years. Clinically this keratinization disorder was characterized by a generalized congenital ichthyosis with a reticulate skin pattern pronounced in a variable degree of severity, also involving the large flexures and the face, palms, and soles. Typical ultrastructural criteria were membrane structures, abnormal vesicular keratinosomes, vesicular complexes, and membrane-bound vacuoles within the cytoplasm of the granular cells, partly retained in the horny layer. A successful therapy with retinoids resulted in a complete removal of the hyperkeratoses but left the striking skin pattern unchanged. The morphological peculiarities remained unaltered as well. They are independent of the localization of the biopsies, of age and sex of the patients, and of oral and local treatment. Based on the clinical and ultrastructural features, this scaling disorder can be delineated against all other inherited ichthyoses and was termed ichthyosis congenita type III. A new nomenclature contributing to a distinct classification within the heterogeneous ichthyosis congenita group is discussed.Dedicated to Professor Urs W. Schnyder, Zürich, on the occasion of his 65th birthday     

Ultrastructural features resembling those of harlequin ichthyosis in patients with severe congenital ichthyosiform erythroderma

Congenital ichthyoses are a group of heterogeneous disorders of cornification. Autosomal recessive congenital ichthyosis (ARCI) can be clinically subdivided into congenital ichthyosiform erythroderma and lamellar ichthyosis. Ultrastructurally, ARCI is classified into four groups: ichthyosis congenita (IC) types I-IV. The genetic background of the ARCI disorders is heterogeneous, but only one disease gene, transglutaminase 1, has been detected so far. We describe six patients with severe congenital ichthyosis from six different Scandinavian families. They could not be classified ultrastructurally into the four IC groups because of atypical findings of electron microscopy. These included abnormal lamellar bodies, alterations in keratohyalin, remnant organelles and lipid inclusions in the upper epidermal cells, which resembled the ultrastructural findings of harlequin ichthyosis (HI), although the HI phenotype was not present at birth. Some clinical features, such as thick scales, erythroderma, alopecia and ectropion were common to all patients. Ichthyosis was usually accentuated in the scalp and four patients had clumped fingers and toes. None of the patients carried the transglutaminase 1 mutation. We conclude that ultrastructural findings resembling those detected in previous HI cases (type 1 and 2) can also be found in patients who do not have classic clinical features of that rare ichthyosis. This may be due to lack of specificity of ultrastructural markers for HI or to its clinical heterogeneity.     

Ichthyoses: differential diagnosis and molecular genetics

Ichthyoses are a heterogeneous group of cornification disorders characterized by a generalized scaling of the skin. Common types such as ichthyosis vulgaris and X-linked recessive ichthyosis manifest after birth. In contrast, rare congenital ichthyoses are inherited diseases, which at birth typically present collodion membranes or ichthyosiform erythroderma. Syndromic ichthyoses display a variety of outstanding associated non-cutaneous symptoms. Because of their rarity these disorders often pose a diagnostic challenge for the clinician. This review discusses a broad spectrum of 13 isolated types of ichthyoses, 11 different syndromes with associated ichthyosis and four related cornification disorders. The clinical, ultrastructural and biochemical characteristics are described along with the different molecular causes of ichthyosis. Special attention is given to lamellar ichthyosis and non-bullous congenital ichthyosiform erythroderma. The different pathomechanisms causing ichthyosis provide a fascinating insight into the role of various proteins, enzymes, lipids and metabolic pathways involved in terminal epidermal differentiation/keratinisation.     

A mother and two children with nonbullous congenital ichthyosiform erythroderma

A mother and her two daughters were all afflicted by congenital nonbullous ichthyosis. The clinical and ultrastructural picture are in accordance with recessive congenital ichthyosiform erythroderma. The mode of inheritance for the children is assumed to be by pseudo-dominance. Nonbullous congenital ichthyosiform erythroderma and lamellar ichthyosis are probably heterogeneous.     

Ichthyosis congenita type IV: a new case resembling diffuse cutaneous mastocytosis

The wide phenotypical heterogeneity within the ichthyosis congenita group of diseases is well known. We report a case of a very rare and unusual autosomal recessive ichthyosis congenita, type IV, according to the ultrastructural classification. Our case presented the triad clue for the diagnosis, characterized by follicular hyperkeratosis, prematurity and perinatal complications, but the clinical diagnosis was further complicated by hypereosinophilia and a strongly positive Darier's sign suggesting diffuse cutaneous mastocytosis. The diagnosis was provided only by electron microscopy, which showed the pathognomonic markers of ichthyosis congenita type IV, namely a large number of membrane structures in the stratum corneum and stratum granulosum. As a consequence, correct genetic counselling for the parents was carried out, and they were informed about the benign course of the disease after the complications of the perinatal period. This case is a further example of the reliability of ultrastructural markers in the diagnosis of inherited keratinization disorders, especially those with an unusual clinical appearance.     

Clinical,light and electron microscopic features of recessive ichthyosis congenita type III

Summary The recessively inherited congenital ichthyoses have ultrastructural features which indicate abnormal epidermal lipid metabolism. The ultrastructural markers of the three recessive congenital ichthyosis groups are lipid droplets in horny layers (type I), cholesterol clefts (type II) and membrane structures (type III). We describe six patients from five families belonging to the last group. The variable clinical phenotype alone does not allow the delineation of this disease, but together with the ultrastructural characteristics the subtype is unequivocal. In addition to the membrane structures, half of the cases showed abnormal keratinosomes and vesicular complexes. Membrane-bound vacuoles and needle-like slits were exceptionally found. The onset of the ichthyosis was variable, in contrast to other patients described under the heading recessive congenital ichthyosis.Part of this investigation was presented at the 18th Annual Meeting of the Society for Cutaneous Ultrastructure Research and Japanese Society for Ultrastructural Cutaneous Biology, Vienna, 25 May 1991     

Altered expression of immunoreactive involucrin in lamellar ichthyosis

In some cases of lamellar ichthyosis, mutations in the epidermal transglutaminase gene and a reduction in the thickness of the cornified envelope have been documented. Involucrin is a major component of the cornified envelope and a substrate for epidermal transglutaminase. The aim of the present work was to analyse the expression of involucrin in lamellar ichthyosis. An ultrastructural study and/or immunohistochemical and biochemical techniques with anti-involucrin antibody were carried out on the epidermis of fifteen patients (12 families) suffering from lamellar ichthyosis. The effect of in vivo retinoid treatment on the involucrin epidermal expression was also investigated. Four cases with normal skin, seventeen cases of other ichthyoses and ten cases of psoriasis were used as controls. In all these cases of lamellar ichthyosis, a thin or absent cornified envelope, electron-dense granules inside corneocytes and a decrease of the epidermal involucrin expression were observed. In the patients receiving treatment with retinoids, western blot and ELISA revealed an increase in the involucrin expression. The decreased expression of involucrin in lamellar ichthyosis could contribute to the altered desquamation process accompanying the disease, since the clinical improvement associated with retinoid treatment is accompanied by an increase in the expression of involucrin.     

A longitudinal study of a harlequin infant presenting clinicallyas non-bullous congenital ichthyosiform erythroderma

Over the past 8 years, we have followed a child born as a harlequin baby, who survived due to treatment with retinoids. His condition evolved clinically towards the erythrodermic form of lamellar ichthyosis (non-bullous congenital ichthyosiform erythroderma, NBCIE). According to ultrastructural and biochemical criteria, our patient originally presented with type II harlequin ichthyosis. Investigations showed an abnormal keratinosome structure and extrusion, a keratin pattern characteristic for epidermal hyperproliferation, and an absence of conversion of profilaggrin to filaggrin. Persisting keratinocyte hyperproliferation, associated with the presence of a dermal infiltrate, is in agreement with the present clinical picture of severe NBCIE. However, abnormal lamellar body production and defective filaggrin processing, which is not one of the diagnostic criteria of NBCIE, persist in the patient's skin. Further studies of the epidermal lipid composition, and of possible mutations of the keratinocyte transglutaminase gene performed on epidermal cell cultures of harlequin ichthyosis, will be necessary before type II harlequin ichthyosis can be accepted as an extremely severe form of NBCIE.     

Acquired peeling skin syndrome in an adult

BACKGROUND: Peeling skin syndrome is a rare form of congenital ichthyosis. The term was coined in 1982 by Levy and Goldsmith and the syndrome is clinically characterized by generalized scaling. Histologically, there is an epidermal separation in the stratum corneum. CASE REPORT: We report the case of a 73-year-old woman who had ichthyosis without cicatricial progressive alopecia since her first pregnancy. An ultrastructural study was performed confirming the clinical diagnosis of peeling skin syndrome. DISCUSSION: The peeling skin syndrome designates several different clinical entities classed by Traupe in type A and type B. Mevorah and al. expanded this classification with a type C. This classification has remained valid after additional information provided by ultrastructural studies and may suggest different pathogenic mechanisms underlying the dermatosis. A critical review of the literature shows that the case reported here is exceptional and had a late clinical onset.     

常染色体隐性遗传性鱼鳞病一家系表型、基因型与皮损超微结构研究

目的 探讨常染色体隐性遗传性鱼鳞病家系临床表型、基因型及超微结构。方法 观察常染色体隐性遗传性鱼鳞病患者临床表现。用PCR扩增TGM1基因15个外显子及其邻近剪切位点,双向直接测序;取先证者背部皮损做透射电镜观察,记录电镜表现特征。结果 先证者临床表现介于板层状鱼鳞病及非大疱性鱼鳞病样红皮病之间,其弟弟为火棉胶婴儿。先证者、其弟及父亲3号外显子第551位碱基胞嘧啶（C）→胸腺嘧啶（T）,其编码的第143位氨基酸由精氨酸变为半胱氨酸（R143C）;先证者、其弟及母亲4号外显子第759位胞嘧啶（C）→胸腺嘧啶（T）,使第212位氨基酸由丝氨酸转变为苯丙氨酸（S212F）。电镜观察发现,先证者皮损不仅有Ⅱ型结构表现,也同时存在Ⅲ型结构特征。结论 该家系患者携带复合杂合突变,R143C属于热点区,S212F为新发现的位点。携带TGM1基因突变的先证者皮损电镜表现为Ⅱ型,但同时发现有Ⅲ型结构存在。     

Congenital ichthyosis with hypogonadism and growth retardation — a new syndrome with peculiar ultrastructural features

Summary A male patient presented with a congenital ichthyosis clinically characterized by generalized erythroderma, fine scaling on the trunk and palmoplantar hyperkeratoses with severely affected nails. The acanthotic epidermis was characterized by hyperproliferation with a large quantity of mitoses and extremely suppressed keratinization without a normal granular layer. The horny layer was parakeratotic and contained remnants of cell debris and lipid droplets. Ultrastructurally the prickle cell layer was characterized by binuclear cells, oedematization of the keratinocytes and isolated dyskeratotic cells. Some suprabasal cells showed unusual morphological features, containing nuclei with cytoplasmic pseudoinclusions, sometimes leading to a complete disintegration of the nuclear structure, and bowl- and lens-shaped accumulations of a filamentous material. Instead of normal tonofibrils, the aggregated material consisted of fine interlacing filaments. The latter are compared with the filamentous shells in ichthyosis hystrix Curth-Macklin and congenital reticular ichthyosiform erythroderma. The clinical symptomatology — congenital ichthyosis, growth retardation, secondary hypogonadism, hepatomegaly — and the ultrastructural characteristics of the keratinization disorder indicate that the present case cannot be considered as a subtype of the recessively inherited ichthyosis congenita group, but suggest a new syndrome as a separate nosologic entity.     

An autosomal recessive exfoliative ichthyosis with linkage to chromosome 12q13

A new variant of congenital exfoliative ichthyosis in two related Bedouin families is reported. The ichthyosis appeared shortly after birth as a fine peeling of nonerythematous skin on the palms and soles. The prominent well-demarcated areas of denuded skin in moist and traumatized regions resembled the 'mauserung' phenomenon of ichthyosis bullosa of Siemens (IBS). Unlike in IBS, epidermolysis is absent on histological examination. Electron microscopy revealed a prominent intercellular oedema and numerous aggregates of keratin filaments in basal keratinocytes. Abnormal keratin (K) 1 expression was seen in the affected epidermis; however, all other keratins, including K2e, had a distribution comparable to that seen in normal controls. A maximum two-point LOD score of 2.53 and multipoint LOD score of 3.76 were obtained for marker D12S390, suggesting linkage to the type II keratin cluster on chromosome 12q13. Sequencing of both the K1 gene, the promotor and the 3' calcium regulatory region did not reveal a mutation. K2e and K5 genes, as well as the genes harboured within the minimal region, such as retinoic acid receptor gamma, sterol O-acyltransferase 2, integrin beta7 and insulin-like growth factor binding protein-6, were also excluded. This combination of clinical, histological, ultrastructural and genetic features has not been previously reported in other congenital exfoliative ichthyoses. We therefore suggest that it represents a new form of exfoliative ichthyosis.     

Ultrastructural changes in the epidermis in ichthyosis vulgaris

Electron-microscopic examinations of the epidermis in 11 patients suffering from xeroderma with autosomal dominant and X-recessive inheritance have revealed changes in the basal membrane, scarce pinocytotic vesicles near the basal membrane, inter- and intracellular edemas in the epidermis, a decrease of the desmosomal contacts and an increased number of microvilli on the epidermocytes of the basal and prickle-cell layers, condensation of the nucleoplasm, reduced counts of organelles and condensation of the epidermocyte tonofilaments, hyperkeratosis, and an elevated count of the desmosomes in the horny layer in both forms of ichthyosis. Autosomal dominant ichthyosis is characterized by the presence of just few intact, or by complete absence of keratohyalin granules in the granular layer. The detected ultrastructural signs may be used in the differential diagnosis between various ichthyosis forms and may contribute to deciphering the pathogenetic mechanisms of impairment of keratinization in this hereditary dermatosis.     

A new variant of autosomal recessive exfoliative ichthyosis

We report unusual congenital ichthyosiform dermatosis in 5 of 12 children in two related families of unaffected, consanguineous Bedouin parents. It appeared shortly after birth as a fine peeling of nonerythematous skin on palms and soles. Gradually it evolved into prominent, well-demarcated areas of peeling skin in moist and traumatized regions. The cutaneous manifestations share features of ichthyosis bullosa of Siemens (IBS) and peeling skin syndrome (PSS). Histologic examination revealed orthokeratosis, a thickened granular cell layer, and spongiosis without epidermolytic hyperkeratosis. On electron microscopy there was prominent intercellular edema and numerous aggregates of keratin filaments in basal keratinocytes. This combination of clinical, histologic, and ultrastructural features has not been previously reported in the heterogeneous group of congenital ichthyoses. We suggest that it represents a new variant of exfoliative ichthyosis.     

Ictiosis congénitas autosómicas recesivas

The term autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare disorders of keratinization classified as nonsyndromic forms of ichthyosis. This group was traditionally divided into lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) but today it also includes harlequin ichthyosis, self-healing collodion baby, acral self-healing collodion baby, and bathing suit ichthyosis.The combined prevalence of LI and CIE has been estimated at 1 case per 138 000 to 300 000 population. In some countries or regions, such as Norway and the coast of Galicia, the prevalence may be higher due to founder effects. ARCI is genetically highly heterogeneous and has been associated with 6 genes to date: TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22, and ABCA12. In this article, we review the current knowledge on ARCI, with a focus on clinical, histological, ultrastructural, genetic, molecular, and treatment-related aspects.     

The clinical spectrum of nonbullous congenital ichthyosiform erythroderma and lamellar ichthyosis

Until about 20 years ago, the term lamellar ichthyosis (LI) represented all nonbullous autosomal recessive ichthyoses except for harlequin ichthyosis and ichthyosis syndromes. Since the 1980s, nonbullous autosomal recessive ichthyoses have been divided into two major clinical entities, nonbullous congenital ichthyosiform erythroderma (NBCIE) and LI. The nature of scaling and intensity of erythroderma are important clinical features that distinguish between NBCIE and LI. However, a considerable number of cases show an intermediate phenotype between the two classic clinical features. Histologically, parakeratosis and inflammatory cell infiltration are seen more frequently in NBCIE than in LI and the stratum corneum is usually thicker in LI than in NBCIE. However, neither histopathological findings nor ultrastructural features seem to help clearly distinguish between NBCIE and LI. Mutations in any of the three known causative genes, TGM1, ALOXE3 or ALOX12B, can lead either to NBCIE or LI. Candidate genes specific to either NBCIE or LI alone have not been identified. Based on these facts, it might be better to consider NBCIE and LI as variations of a single keratinization disorder, although the classification of these autosomal recessive congenital ichthyosis patients into NBCIE or LI depending on their clinical features is still useful for practical patient management.     

New observations on the fine structure of lamellar ichthyosis and the effect of treatment with etretinate

Light and electron microscopy were used to study specimens from four patients suffering from lamellar ichthyosis. Three of these patients had been treated with etretinate for 10 months. Biopsy specimens taken from the patients before treatment showed hyperkeratosis with focal parakeratosis, a thickened granular layer in which the cellular content of tonofibrils and keratohyalin was moderately diminished, and acanthosis with increased cellular activity. During treatment with etretinate there was moderate clinical improvement. The most conspicuous microscopic change was thinning of the cornified layer. The intercellular spaces of the epidermis showed increased amounts of fine and coarse granular substance. The number of keratinosomes was increased. Stimulation of Langerhans' cells was observed. Two new ultrastructural findings in lamellar ichthyosis were discovered. First, the marginal band of the cornified layer was absent in conventional glutaraldehyde-osmium tetroxide fixation. Second, the corneocytes contained electron-lucent crystals. The treatment with etretinate did not influence these structures. The mechanism of action of retinoids in lamellar ichthyosis is discussed.     

Ichthyosis hystrix with parakeratosis in the form of cornoid lamellae

We report on a keratinization disorder in four brothers in a family in which members had been affected in three generations. Clinical signs and genetic, histopathologic, autoradiographic and ultrastructural examinations all support the diagnosis of hystrixlike, proliferative ichthyosis with cornoid lamellae and autosomal dominant inheritance. The relationship of the disorder to other hystrixlike genetic keratinization disorders is discussed.     

The Keratinization Disorder in Collodion Babies Evolving into Lamellar Ichthyosis*

Two collodion baby girls with disorder evolving into lamellar ichthyosis were followed by light and electron microscopy. Light microscopically, the neonatal collodion skin was characterized by a thick compact stratum corneum which was PAS positive in its upper two thirds, by a thin stratum granulosum and by a non-acanthotic stratum spinosum with normal mitotic activity. Electron microscopically, the upper stratum corneum appeared pathological, whereas the lower part was normal except for some minor parakeratosis. The main alterations in the underlying stratum granulosum were diminished tonofibrils and keratohyalin. Biopsy specimens taken at the age of 2 weeks were typical for lamellar ichthyosis and showed hyperkeratosis with focal parakeratosis, a thickened stratum granulosum in which the cellular content of keratohyalin and tonofibrils was moderately diminished, and acanthosis with increased mitotic activity. It appears that the ultrastructural changes of the stratum granulosum, seen in lamellar ichthyosis, are already present in the collodion skin of the newborn, at a time when the epidermis does not yet show an increase in mitotic activity.