| #242100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ICHTHYOSIFORM ERYTHRODERMA, CONGENITAL, NONBULLOUS, 1; NCIE1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| IECN1 ICHTHYOSIFORM ERYTHRODERMA, BROCQ CONGENITAL, NONBULLOUS FORM NONBULLOUS CONGENITAL ICHTHYOSIFORM ERYTHRODERMA 1 NCIE CIE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because nonbullous congenital ichthyosiform erythroderma (NCIE) can be caused by mutation in the transglutaminase-1 gene (TGM1; 190195), the 12R-lipoxygenase gene (ALOX12B; 603741), and the lipoxygenase-3 gene (ALOXE3; 607206). A rare form of NCIE, Chanarin-Dorfman syndrome (275630), is caused by mutation in the ABHD5 gene (604780). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nomenclature | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The term lamellar ichthyosis (LI; see 242300) was initially used for all nonbullous autosomal recessive ichthyoses except for harlequin ichthyosis (242500) and ichthyosis syndromes, but since the 1980s the nonbullous autosomal recessive ichthyoses have been divided into 2 major clinical entities, nonbullous congenital ichthyosiform erythroderma and LI (Williams and Elias, 1985; Akiyama et al., 2003). A considerable number of cases, however, show an intermediate phenotype, and neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in the TGM1 and ichthyin (NIPAL4; 609383) genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes. Akiyama et al. (2003) suggested that NCIE and LI might be considered to be variations of a single keratinization disorder, although the authors acknowledged that the distinction is useful for clinical management. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nonbullous congenital ichthyosiform erythroderma is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. As many as 90% of affected individuals present at birth as collodion babies. Patients suffer from 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, eclabion, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis. Histologic features such as hyperkeratosis, an increase in stratum corneum thickness, a normal or prominent granular layer, and increased mitoses point to a hyperproliferative epidermal defect. Prominent dermal blood vessels and an upper dermal lymphocytic infiltrate may explain the erythroderma (Fischer et al., 2000). MacKee and Rosen (1917) reviewed the subject of congenital ichthyosiform erythroderma. Wile (1924) reported 3 affected males, the offspring of matings in which 2 brothers married 2 sisters, who were their first cousins. Arce and Berchmans (1969) described ichthyosiform dermatosis in 13 members of an inbred Brazilian kindred. Heimendinger and Schnyder (1962) distinguished 2 types of congenital ichthyosiform erythroderma, one inherited as an autosomal dominant and the other as an autosomal recessive trait. The recessive form is nonbullous and is associated with growth retardation, oligophrenia, spastic paralysis, genital hypoplasia, hypotrichia, and shortened life-expectancy. In the autosomal dominant or bullous form (113800), however, life-expectancy is not shortened and the associated symptoms include only seborrhea of the head and probably polydipsia. Both types begin at birth and are localized mostly on the flexor surfaces. Rossmann-Ringdahl et al. (1986) described this disorder in a woman and both of her children. Although her husband was not known to be related, this was thought to be pseudodominant inheritance. Williams and Elias (1986), however, thought that this might represent a true dominant form of 'lamellar' ichthyosis (146750). They pointed to the kindred reported by Traupe et al. (1984) with affected persons in 3 generations and mentioned a similar family of their own. Rand and Baden (1983) considered recessive lamellar ichthyosis to be synonymous with congenital nonbullous ichthyosiform erythroderma, whereas Wells and Kerr (1965) considered them separate entities. Williams (1983) noted that there may be biochemical differences. The experience of Holbrook et al. (1988) suggested that diagnosis on the basis of the morphology of fetal skin biopsies is fraught with uncertainty. Cruz et al. (2000) reviewed the eyelid abnormalities in 8 patients with lamellar ichthyosis and 2 patients with congenital ichthyosiform erythroderma. All 8 patients presented with cicatricial lagophthalmos (inability to appose the eyelids due to cutaneous scarring). Of the 8 patients with classic LI, 5 had eclabion (ectropion of the eyelid) of all 4 eyelids, 1 had only lower eclabion, and 2 had no eclabion. The 2 patients with NCIE had distinct eyelid abnormalities, including madarosis (eyelash loss) and eyelash retraction. Three patients with classic LI had severe visual loss from corneal damage. Of these 3 patients, 2 did not have upper eclabion. The authors concluded that severe corneal damage and visual loss could occur in LI even in the absence of upper or lower eclabion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 4 Finnish patients with NCIE from 3 families, Laiho et al. (1997) identified compound heterozygosity for missense mutations in the TGM1 gene (see 190195.0004, 190195.0006, and 190195.0008, respectively). The authors identified compound heterozygosity for a missense mutation and an unknown mutation in 3 additional Finnish patients with NCIE from 2 families (see 190195.0008 and 190195.0009, respectively). Jobard et al. (2002) identified mutations in the ALOXE3 and ALOX12B genes in NCIE linked to chromosome 17. A missense (607206.0001), a nonsense (607206.0002), and a deletion (607206.0003) mutation were found in ALOXE3 and a 1-bp deletion (603471.0001) and 2 missense mutations (603471.0002 and 603471.0003) were found in ALOX12B among 6 consanguineous families from the Mediterranean basin. They hypothesized that the product of 1 of these enzymes may be the substrate of the other, and thus function in the same metabolic pathway. Yu et al. (2003) showed that ALOXE3 functions as an epoxy alcohol synthase using the product of ALOX12B as the preferred substrate. Their results provided strong biochemical evidence for a functional linkage of the ALOX12B and ALOXE3 proteins. The 2 are coexpressed in tissues, and either gene can be the site of mutations causing NCIE, indicating a functional relationship. In 17 families with NCIE, Eckl et al. (2005) identified 11 different point mutations in ALOXE3 and 5 in ALOX12B. In vitro functional studies of the mutant proteins revealed that all but 1 of the mutants were enzymatically inactive. The latter L237M mutation in the ALOXE3 gene (607206.0004) was identified in the most severely affected of all the patients, but the recombinant protein showed activity comparable to that of wildtype protein in vitro. Eckl et al. (2005) suggested that there might be in vivo impairment of protein-protein interaction, but the family was unavailable for further study. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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