#113800
ICD+
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| EPIDERMOLYTIC HYPERKERATOSIS; EHK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BULLOUS ERYTHRODERMA ICHTHYOSIFORMIS CONGENITA OF BROCQ BULLOUS CONGENITAL ICHTHYOSIFORM ERYTHRODERMA; BCIE BULLOUS ICHTHYOSIFORM ERYTHRODERMA; BIE EPIDERMOLYTIC ICHTHYOSIS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| EPIDERMOLYTIC HYPERKERATOSIS, LATE-ONSET, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that epidermolytic hyperkeratosis (EHK) can be caused by heterozygous mutation in the keratin-1 gene (KRT1; 139350) and by heterozygous or homozygous mutation in the keratin-10 gene (KRT10; 148080). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Epidermolytic hyperkeratosis (EHK), also termed bullous congenital ichthyosiform erythroderma (BCIE), is a keratinization disorder with an incidence of approximately 1 in 200,000 in the USA. The clinical phenotype of EHK is characterized by erythema and widespread formation of epidermal blisters developing at birth. Later in life, bullous erythema is replaced by progressive hyperkeratosis, involving thickening of the cornified layer of the epidermis (summary by Muller et al., 2006). Goldsmith (1976) used the designation of epidermolytic hyperkeratosis for the condition that is called bullous congenital ichthyosiform erythroderma (BCIE) when generalized, and ichthyosis hystrix (see 146600) when localized. They are presumably distinct entities. A form of epidermolytic hyperkeratosis that is limited to the palms and soles, designated palmoplantar keratoderma (EPPK; 144200), is caused by mutation in the keratin gene KRT9 (607606), and a mild form of EPPK can also be caused by mutation in KRT1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinically, BCIE presents at birth or soon afterwards with widespread erythroderma, blistering, and scaling. Blistering tends to improve with age. Warty thickening of the flexural skin usually appears by the third or fourth year and persists into adult life. There is, in addition, hyperkeratosis of the palms and soles. Life expectancy is usually normal although the disease can be severely incapacitating. Death, often associated with severe infection, may occur in infancy (review by Eady et al., 1986). Heimendinger and Schnyder (1962) described this disorder in a man and 2 of his 3 children, a son and a daughter. Among 17 families with 2 or more affected persons, Gasser (1964) found only sibs affected in 2 families, 2 successive generations affected in 12, and 3 generations affected in 3. The variation in the height of the scale along normal skin markings in this disorder produces a ridgelike appearance, particularly in the bends of the elbows and knees, that has led to the designation 'porcupine man;' see 146600. The rate of new cell formation is abnormally high; keratinocytes traverse the epidermis from the basal layer to the stratum corneum in as little as 4 days, a journey that takes 2 weeks in normal skin. Several kindreds have been reported in which the first affected member, presumably a mosaic for the new mutation, had linear or patchy lesions and produced children with generalized bullous ichthyosiform erythroderma (Epstein, 1992). Epstein (1992) suggested that the 'porcupine man' may have had BCIE. Autosomal Recessive Epidermolytic Hyperkeratosis Muller et al. (2006) reported a consanguineous family in which 2 of 4 sibs had EHK. Both affected sibs showed collodion skin and generalized erythroderma at birth, and in the months after birth, developed erosions after mild mechanical trauma and progressive ichthyosis. At the time of examination, the affected sibs exhibited generalized hyperkeratosis, which was pronounced over the large joints and the volar surfaces of the elbows and knees, with palmoplantar sparing. The 8-year-old boy showed conspicuous cobblestone morphology of the hyperkeratosis in his neck area, and his 6-year-old sister had erythema and hyperkeratosis as well as spontaneous erosions on her back. Their first-cousin parents and 2 other sibs were clinically unaffected. Histopathologic examination of skin biopsies from the affected children revealed hyperkeratosis, acanthosis, and papillomatosis, with vacuolar degeneration of the keratinocytes in the suprabasal epidermal layers and coarse keratohyaline granules within the thickened granular layer. Electron microscopy at low magnification showed cell morphology similar to that of autosomal dominant EHK, with the hallmark clumps of loose and irregularly shaped electrodense material, corresponding to aggregates of keratin intermediate filaments, in the suprabasal epidermal layers. At higher magnifications, however, the perinuclear shells often seen in autosomal dominant EHK patients were absent, and the keratin clumps had a nearly homogeneous, amorphous structure, in contrast to the keratin clumps in autosomal dominant EHK which have a filamentous, thready appearance. Electron microscopy of skin from the clinically unaffected mother showed no ultrastructural abnormalities of the epidermal keratinocytes. Tsubota et al. (2008) reported a Turkish girl with mild BCIE, born of first-cousin parents, who at birth had widespread, diffuse skin blistering and erosive lesions. At 3 years of age, she was still developing skin erosions at sites of trauma, primarily on the face and trunk, and had brownish hyperkeratotic lesions over her chest, arms, back, and knees, as well as scaly keratotic lesions on her scalp. Plamoplantar surfaces were not affected, and nails, hair, and teeth were normal, as was psychomotor development. Her parents and 3 sibs were clinically unaffected, and there was no family history of skin diseases. Electron microscopy showed disruption of the keratin filament network only in the uppermost keratinocytes of the spinous and granular layers, where irregularly shaped keratin clumps and cytolysis were seen; perinuclear shells of clumped keratin filaments were absent. Terheyden et al. (2009) described a girl with severe EHK from a consanguineous family of Sudanese descent, who at birth had widespread erythema and superficial erosions of the face, trunk, and proximal extremities. In the first few days of life, she became increasingly lethargic and developed hypernatremia, requiring intensive neonatal care. Histopathology of a skin biopsy taken shortly after birth was typical for EHK, showing vacuolar degeneration of suprabasal keratinocytes and coarse keratohyalin granules in the thickened granular layer. Electron microscopy showed cytolysis and loose, irregularly shaped electrodense clumps within the keratinocytes of the suprabasal layers of the epidermis; the authors noted that the clumps had a nearly homogeneous, amorphous structure, in contrast to the filamentous, thready appearance of clumps seen in autosomal dominant EHK. Terheyden et al. (2009) concluded that a characteristic ultrastructural picture of sparse keratin filaments and keratin clumps with a nearly homogeneous, amorphous structure should prompt detailed analysis of the pedigree for consanguinity and recessive inheritance. Covaciu et al. (2010) reported an infant, born of first-cousin North African parents, who had lethal epidermolytic ichthyosis. At birth the patient had superficial, erythematous, nonbleeding erosions, delimited by easily detachable epithelial sheets, that covered 70% of the body surface, with no intact blisters seen. Hair and nails were not affected. Sepsis and hypernatremic dehydration were early complications, and the patient died at 3 days of age due to disseminated intravascular coagulation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inheritance | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Epidermolytic hyperkeratosis is usually transmitted following an autosomal dominant inheritance pattern (see Heimendinger and Schnyder, 1962; Gasser, 1964), while EHK rises from sporadic mutations in up to 50% of cases. Covaciu et al. (2010) stated that the existence of a rare form of autosomal recessive EHK has a major impact in genetic counseling. Until now, in sporadic cases, the exclusion of features of EHK in the parents significantly lowered recurrence risk; however, the existence of an autosomal recessive form may increase the recurrence risk from less than 1% to as high as 25% in specific cases, especially in the presence of consanguineous parents. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pathogenesis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tonofibrils are fibrillar structural proteins in keratinocytes. They are the morphologic equivalent of the biochemically well-characterized prekeratin and precursors of the alpha-keratin of horn cells. Anton-Lamprecht (1978) stated that 4 genetic disorders of keratinization are known to have a structural defect of tonofibrils. (1) In the harlequin fetus (242500), an abnormal x-ray diffraction pattern of the horn material points to a cross-beta-protein structure instead of the normal alpha-protein structure of keratin. (2) Bullous ichthyosiform erythroderma is characterized by an early formation of clumps and perinuclear shells due to an abnormal arrangement of tonofibrils. (3) In the Curth-Macklin form of ichthyosis hystrix (146590), concentric unbroken shells of abnormal tonofilaments form around the nucleus. (4) In ichthyosis hystrix gravior (146600), only rudimentary tonofilaments are found with compensatory production of mucous granules. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prenatal Diagnosis Golbus et al. (1980) achieved prenatal diagnosis by fetal skin biopsy through the amnioscope. See also Anton-Lamprecht (1981). Eady et al. (1986) achieved prenatal diagnosis of BCIE at 20 weeks' gestation by electron microscopic identification of the characteristic aggregates of tonofilaments within skin-derived amniocytes and in fetal skin. The mother was affected, an earlier born child was severely affected and died at 6 days of age with generalized candidiasis, and the fetus that was diagnosed as affected was aborted at 21 weeks. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The changes in the suprabasal keratinocytes in BCIE resemble those in the basal keratinocytes in epidermolysis bullosa simplex (EBS; see 131760) in which keratin mutations have been identified (e.g., 148066.0001). In both diseases, the intermediate filament (IF) aggregates contain the keratins normally present in the particular cells: keratins 5 and 14 in the basal cells of Dowling-Meara EBS and keratins 1 and 10 in the suprabasal cells of BCIE. This fact prompted Epstein (1992) and his colleagues to use linkage analysis to test whether keratin gene mutations might also underlie BCIE. Bonifas et al. (1992) indeed found that the BCIE phenotype was linked to markers in the 12q region containing genes encoding type II keratins. Expression of a modified truncated human keratin-10 gene (KRT10; 148080) in transgenic mice gives rise to skin with the morphologic and biochemical characteristics of epidermolytic hyperkeratosis. As in KRT5 and KRT14 mutations that give rise to epidermolysis bullosa, mutant KRT10 interferes with proper filament network formation and leads to cell degeneration, but in this case the phenotype is manifested in the suprabasal layers of the epidermis. As epidermal cells differentiate, KRT1 and KRT10 protein levels increase, and KRT14 and KRT5 protein levels decrease. Therefore, as differentiation proceeds, an increasing gradient of mutant/wildtype keratin is established, yielding epidermal layers with progressively greater levels of filament disorganization and cell degeneration. Compton et al. (1992) demonstrated complete linkage of epidermolytic hyperkeratosis with the KRT1 gene on 12q11-q13. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a mother and son with epidermolytic hyperkeratosis, Rothnagel et al. (1992) identified heterozygosity for a missense mutation in the KRT1 gene (E310Q; 139350.0001). In another mother/son pair and an unrelated 17-year-old male with EHK, the authors identified heterozygosity for 2 missense mutations in the KRT10 gene, L15S (148080.0002) and R10H (148080.0001), respectively. In the family with EHK in which Compton et al. (1992) demonstrated linkage to the type II keratin gene cluster on 12q, Chipev et al. (1992) identified a missense mutation in the KRT1 gene (L160P; 139350.0002). Chipev et al. (1992) also found the R10H mutation in KRT10 in 2 EHK families. In 2 of 6 unrelated probands with EHK, Cheng et al. (1992) identified heterozygosity for a missense mutation in the KRT10 gene (R156H; 148080.0003) that segregated with disease in family members and was not found in 206 control chromosomes. In a patient with severe EHK, Syder et al. (1994) identified a missense mutation in the KRT1 gene (Y481C; 139350.0003). Letai et al. (1993) reported that clinical severity of EHK and epidermolysis bullosa simplex (EBS) is related to the location of point mutations within the keratin polypeptides and the degree to which these mutations perturb keratin IF structure. Point mutations in the most severe forms have been clustered in the highly conserved ends of the KRT5 or KRT14 rod domains in EBS (e.g., 148066.0002) and in the corresponding regions of the KRT10 and KRT1 rod domains in EHK (e.g., 148080.0003). Mutations in milder cases have been found in less-conserved regions, either within or outside the rod domain. Of 11 known EBS or EHK mutations, 6 affected a single, highly evolutionarily conserved arginine residue which, when mutated, markedly disturbs keratin filament structure and network formation. The site also appeared to be a hotspot for mutation by CpG methylation and deamination. Letai et al. (1993) suggested that arg156 of KRT10 and arg125 of KRT14 must play a special role in maintaining keratin network integrity. Palmoplantar keratoderma (PPK; see 144200) is a more prominent feature of patients with BCIE with mutations in KRT1 than in those with mutations in KRT10 (DiGiovanna and Bale, 1994), possibly because keratin-1 is the main expression partner of keratin-9 (607606) in palmoplantar epidermis. Sprecher et al. (2003) reported a 17-year-old male of Chinese ancestry who had an unusual variant EHK phenotype. His skin appeared normal at birth and during infancy. At 2 years of age, the skin of palms and soles became thickened and he developed well-demarcated, yellowish hyperkeratotic plaques over the ankles, elbows, and knees. Islands of superficial peeling reminiscent of the 'mauserung' phenomenon in ichthyosis bullosa of Siemens (146800) were observed on the skin of the trunk and the extensor surface of the legs. The disease progressively worsened during childhood. Histologic examination of a skin biopsy revealed marked orthokeratotic hyperkeratosis, papillomatosis, and acanthosis. Occasional foci of vacuolated cells and binucleated cells were observed in the upper spinous and granular layers. Electron microscopy demonstrated fractured and shortened keratin intermediate filaments (KIFs) that remained connected to the desmosomes, occasional KIF clumping, and abnormalities of the extracellular lamellar bilayers. Sprecher et al. (2003) determined that this individual was heterozygous for a single-nucleotide insertion (1752insG; 139350.0015) in the KRT1 gene. Mosaicism Epidermal nevi (162900) appear at or shortly after birth as localized epidermal thickening with hyperpigmentation that frequently follow the lines of Blaschko, suggesting that they result from postzygotic somatic mutation in the skin. A rare subgroup of epidermal nevus is clinically indistinguishable from other epidermal nevi, but displays histopathologic features typical of epidermolytic hyperkeratosis, with normal basal cells and suprabasal cells that show clumping of the keratin filaments that make up the structural framework of the epidermal keratinocyte (Anton-Lamprecht, 1983). Patients with this type of epidermal nevi sometimes have offspring with generalized EHK (Paller et al., 1994). Nazzaro et al. (1990) reported 2 unrelated families in both of which a child with generalized EHK had a parent with linear epidermolytic hyperkeratosis, otherwise known as epidermolytic epidermal nevus. Gonadal mosaicism was postulated by Nazzaro et al. (1990). Eng et al. (1991) observed an 8-year-old Puerto Rican boy with epidermolytic hyperkeratosis of Brocq showing diffuse involvement of the changes typical of this disorder as well as a systematized linear pattern of 'hyperpigmented, hyperkeratotic and hypopigmented swirls' covering large parts of his body. Happle and Konig (1999) suggested that this represents a phenomenon of twin spotting with some patches of excessive involvement and others with absent involvement. They speculated that during embryogenesis, somatic recombination gave rise to 2 different daughter cells. One of them had become homozygous for a mutation (in either keratin-1 or keratin-10), resulting in bands of expressively involved hyperkeratotic skin, whereas the other cell had become homozygous for the wildtype allele, resulting in bands of expressively involved hyperkeratotic skin, whereas the other cell had become homozygous for the wildtype allele, resulting in bands of hypopigmented healthy skin. The encountering of some epidermolytic foci within the hypopigmented skin would mirror the fact that mosaic populations of cells often intermingle to some degree. In a family with EHK in which Cheng et al. (1992) had identified an R156H mutation in the KRT10 gene (148080.0003), Paller et al. (1994) found that blood genomic DNA from the grandmother, who had markedly milder EHK and extensive epidermal nevi, showed underrepresentation of the mutation. Analysis of lesional skin revealed the presence of the R156H mutation, whereas no mutation was detected in normal skin. Paller et al. (1994) also analyzed the KRT1 and KRT10 genes in 2 parents with epidermal nevi (linear form of EHK) and 4 of their offspring with EHK from the families originally reported by Nazzaro et al. (1990) and identified heterozygosity for 2 missense mutations in the KRT10 gene, R156C (148080.0010) and M150T (148080.0013), respectively, in all cell types examined from the offspring. Analysis of keratinocytes from the parents' epidermolytic epidermal nevi revealed heterozygosity for the mutations, respectively, which were not found in unaffected skin and were absent or underrepresented in blood and skin fibroblasts from the parents. Paller et al. (1994) concluded that epidermal nevus of the epidermolytic hyperkeratotic type is a mosaic genetic disorder of suprabasal keratin. Happle (1997) noted that an early postzygotic mutation can cause autosomal dominant skin disorders to become manifest in a mosaic form, involving the body in a linear, patchy, or otherwise circumscribed arrangement, in which the segmental lesions usually show the same degree of severity as that found in the corresponding nonmosaic trait. Occasionally, however, the intensity of involvement observed in the circumscribed area is far more pronounced; Happle (1997) suggested that this phenomenon can be explained by delineating a rule of dichotomous segmental manifestations reflecting different states of zygosity. Heterozygosity for the mutation results in severity corresponding to that in the nonsegmental phenotype; loss of heterozygosity for the same allele causes markedly more severe involvement. Happle (1997) pointed to examples of these 2 forms classified by severity, type 1 and type 2 respectively, in epidermolytic hyperkeratosis of Brocq. Except in the area of the epidermal nevus of epidermolytic type, the skin of these mosaic individuals is completely normal. The mosaicism may, however, involve the gonad and such individuals may give birth to children with diffuse epidermolytic hyperkeratosis of Brocq (Nazzaro et al., 1990), which Happle (1997) designated type 1 segmental involvement. Type 2 segmental involvement, he suggested, is represented by patients such as the 21-year-old man reported by Hadlich and Linse (1989) to have typical clinical and histopathologic features of epidermolytic hyperkeratosis of Brocq with an additional feature of a linear verrucous nevus on his left forearm that extended to the dorsal aspect of the hand. Happle (1997) suggested that the linear lesion was an example of type 2 involvement, representing a change from heterozygosity to either homozygosity or hemizygosity for the Brocq mutation. Nomura et al. (2001) studied a 19-year-old boy with severe ichthyosiform erythroderma and prominent palmoplantar hyperkeratosis with digital contractures. His mother exhibited only mild ichthyosiform skin, granular verrucous lesions, and less severe streaky palmoplantar hyperkeratosis. Mutation analysis in the proband showed a KRT1 mutation (139350.0008). In the mother, the same mutation was recognized, but only faintly in the leukocyte DNA, suggesting that she was most likely mosaic for this mutation. These results suggested that mild forms of BCIE may actually represent extensive epidermal nevi/keratin gene mosaicism. Recessive Epidermolytic Hyperkeratosis In 2 affected sibs with EHK, born of first-cousin parents, Muller et al. (2006) identified homozygosity for a nonsense mutation in the KRT10 gene (148080.0019). The clinically unaffected parents and 2 unaffected sibs as well as 3 other unaffected relatives were heterozygous for the mutation, which was not found in 50 controls. In a 3-year-old Turkish girl with mild BCIE, born of first-cousin parents, Tsubota et al. (2008) identified homozygosity for a nonsense mutation in the KRT10 gene (148080.0020); her unaffected parents were heterozygous carriers and the mutation was not found in 50 controls. In a girl with severe EHK from a consanguineous family of Sudanese descent, Terheyden et al. (2009) identified homozygosity for a 1-bp insertion in the KRT10 gene (148080.0021). Unaffected family members were heterozygous carriers of the mutation. In an infant with epidermolytic ichthyosis who was born of consanguineous North African parents and died at 3 days of age, Covaciu et al. (2010) identified homozygosity for a splice site mutation in the KRT10 gene (148080.0022). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Barker and Sachs (1953); Bonifas et al. (1992) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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