Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The ... Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010). NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by Lefevre et al., 2006). In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by Eckl et al., 2005). For a general phenotypic description and discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).
Lefevre et al. (2004) studied 23 patients with congenital ichthyosis from 14 consanguineous families. Fourteen of the patients (60%) were born as 'collodion babies.' Nine patients from 6 of the families had a clinical picture resembling nonbullous ichthyosiform ... Lefevre et al. (2004) studied 23 patients with congenital ichthyosis from 14 consanguineous families. Fourteen of the patients (60%) were born as 'collodion babies.' Nine patients from 6 of the families had a clinical picture resembling nonbullous ichthyosiform erythroderma, presenting with generalized ichthyosis with erythema, fine whitish scaling on the face and trunk, and larger brownish scaling on the neck, buttocks, and legs; the remainder of the patients had a lamellar-like phenotype. Light microscopy of skin biopsies revealed typical histopathologic features in the patients corresponding to either the NCIE or LI phenotype, respectively: patients with the NCIE phenotype showed hyperkeratosis, thickening of the stratum corneum and moderate acanthosis and parakeratosis, with a normal or slightly prominent granular layer and a mild dermal perivascular lymphocytic infiltrate, whereas patients with a lamellar phenotype had significant orthohyperkeratosis, moderate acanthosis, a normal or reduced granular layer, and mild papillomatosis with dilatation of dermal capillaries. All the patients had palmoplantar keratoderma, often yellowish with fissures, and some clubbing of nails. Dahlqvist et al. (2007) studied 27 patients from 18 families segregating autosomal recessive congenital ichthyosis. Only 1 patient had collodion membrane at birth. From infancy, all patients showed moderate to severe generalized ichthyosis with no, mild, or moderate erythema. A few cases of ectropion were seen, and keratoderma on the soles and hypohidrosis developed in most. Several patients had areas of reticulate ichthyosis with brownish hyperkeratosis and scaling on the trunk and in skin folds. The severity of skin symptoms varied within families, and some patients reported cyclical changes in the severity of symptoms. No nail or hair abnormalities were found. - Ultrastructural Features of Autosomal Recessive Congenital Ichthyosis Patients with ARCI have structural changes affecting terminal differentiation and keratinization within the epidermis, which can be seen using electron microscopy (EM). Dahlqvist et al. (2007) stated that about half of patients with ARCI investigated by EM lack unique characteristics of the epidermis, but the remaining patients show defined ultrastructural markers that can be categorized into 4 main patterns: type I is characterized by broad stratum granulosum and numerous lipid vacuoles in corneocytes; type II shows clefts of former cholesterol crystals in stratum corneum; type III is characterized by abnormal lamellar bodies in stratum granulosum and perinuclear, elongated membranes; and type IV shows lipid membrane aggregations in upper epidermal cells. All individuals but 1 studied by Dahlqvist et al. (2007) in whom NIPAL4 mutations were found fulfilled the EM criteria of ARCI EM type III with the characteristics of hyperkeratotic stratum corneum with lamellae that contained low or minimal amounts of lipid droplets. The same layer was characterized by regularly elongated membranes and vesicular complexes interpreted as irregularly processed content of lamellar bodies. The granular cells were characterized by normal keratohyaline, normal lamellar bodies and regularly elongated perinuclear membranes. In addition, specific vesicular complexes were present, as well as electron-lucent vacuoles sometimes containing one or a few smaller vesicles thought to represent abnormal lamellar bodies.
In 23 patients from 14 consanguineous families with nonsyndromic congenital ichthyosis (ARCI), Lefevre et al. (2004) identified 6 homozygous mutations in the NIPAL4 gene (see, e.g., 609383.0001-609383.0002).
Dahlqvist et al. (2007) studied 27 patients from 18 ... In 23 patients from 14 consanguineous families with nonsyndromic congenital ichthyosis (ARCI), Lefevre et al. (2004) identified 6 homozygous mutations in the NIPAL4 gene (see, e.g., 609383.0001-609383.0002). Dahlqvist et al. (2007) studied 27 patients from 18 ARCI families with the specific ultrastructural features of the epidermis that characterize EM type III. Screening for homozygous genomic regions identified a candidate region on chromosome 5q33, which coincides with the site of the NIPAL4 gene, also known as ichthyin. Mutation screening of NIPAL4 revealed 4 different missense or splice site mutations (see, e.g., 609383.0003-609383.0004) in affected members from 16 of 18 (89%) families with these characteristics of ARCI EM type III. One patient who did not fulfill characteristics of ARCI EM type III carried a homozygous NIPAL4 mutation, which indicated that ichthyin deficiency does not necessarily result in structural changes detected as EM type III.