Erythroderma, Ichthyosiform, Congenital Reticular

A number sign (#) is used with this entry because of evidence that congenital reticular ichthyosiform erythroderma (CRIE) is caused by heterozygous mutation in the KRT10 gene (148080) on chromosome 17q21.

Description

Congenital reticular ichthyosiform erythroderma (CRIE), also known as ichthyosis with confetti (IWC), is a rare skin condition characterized by slowly enlarging islands of normal skin surrounded by erythematous ichthyotic patches in a reticulated pattern. The condition starts in infancy as a lamellar ichthyosis, with small islands of normal skin resembling confetti appearing in late childhood and at puberty. Histopathologic findings include band-like parakeratosis, psoriasiform acanthosis, and vacuolization of keratinocytes with binucleated cells in the upper epidermis, sometimes associated with amyloid deposition in the dermis. Ultrastructural abnormalities include perinuclear shells formed from a network of fine filaments in the upper epidermis (summary by Krunic et al., 2003).

Clinical Features

Camenzind et al. (1984) reported 2 unrelated children with what the authors designated as 'confetti-type' ichthyosis. The first was a 14-year-old French boy with congenital ichthyosiform erythroderma who after treatment with topical retinoids in early childhood began to develop islands of white skin on his upper chest that gradually spread downward. The flat white spots were 1 to 2 cm in diameter, with predominance on the trunk and proximal limbs and sparing of the face, as if the patient had been 'sprayed with confetti.' The authors also noted that the boy had a foul odor reminiscent of butyric acid. Treatment with oral retinoids increased the number of white spots, with extension to the lower extremities. Histologic examination was similar for both erythrodermic and white skin, with an irregularly acanthotic epidermis overlaid by orthokeratotic and parakeratotic hyperkeratosis; the granular layer was present in all examined epidermis. The second patient was a 12-year-old Italian girl with congenital ichthyosiform erythroderma who prior to being treated with retinoids had white confetti-like macules of normal-appearing skin similar to the French boy's, except that her macules were clearly depressed relative to adjacent skin. The patient also developed hypertrichosis on her legs at 3 years of age. Histologic examination of erythematous skin showed epidermal hyperplasia, absence of the granular layer, and parakeratotic hyperkeratosis. Examination of a white macule revealed normal skin, with a granular layer, orthokeratotic horny layer, and normal thickness of the epidermis. Treatment with retinoids resulted in an increase in the number and area of white macules.

Brusasco et al. (1994) restudied the Italian girl originally described by Camenzind et al. (1984). At 18 years of age, she had bright red skin with discrete hyperkeratosis and pityriasiform desquamation, as well as striking patches of apparently normal skin on the trunk enclosed by the erythematous scaling skin. The areas of normal skin, which did not follow any particular distribution, were slightly elevated and the adjacent red ichthyotic skin had a reticulate pattern. Small white patches were also present on the limbs and face. Palmoplantar surfaces were orange-red and hyperkeratotic with increased markings, and there was clubbing of the nails. In addition, the patient had remarkable hypertrichosis, especially on the limbs, and also presented a mild ectropion. Extracutaneous abnormalities were not detected, and all laboratory tests, including hormonal levels, were normal. Punch biopsy of a patch of normal skin showed only mild orthokeratotic hyperkeratosis, whereas the erythrokeratotic skin showed parakeratotic hyperkeratosis, absence of the stratum granulosum, acanthosis, several mitoses, perinuclear vacuolization of some keratinocytes in the superficial layers of the epidermis, a few binuclear keratinocytes, dilation of dermal vessels, and a mononuclear infiltrate in the superficial dermis. Ultrastructurally, the most significant finding was the presence of granular material deposited in the form of cup- or bowl-like perinuclear masses in the vacuolized superficial keratinocytes and binuclear keratinocytes. This material, which closely resembled glycoproteins, was composed of very thin interlacing filaments with the prominent cross-points causing the granular appearance. Brusasco et al. (1994) noted that the ultrastructural findings in this patient presented strong similarities to those of CRIE, defined by a peculiar pattern involving a 3-dimensional network of fine interdigitating filaments forming perinuclear shells in vacuolized keratinocytes of the upper epidermis. Based on clinical, light microscopic, and ultrastructural features, they concluded that 'ichthyosis with confetti' and CRIE are the same disorder. In a further report of this Italian woman at age 23, Brusasco et al. (1998) noted that she had developed several hyperpigmented 3- to 5-mm macules on the extensor surfaces of her limbs. These lesions were almost black and had a tendency to coalesce into dark irregular areas. They were localized on the red ichthyotic skin only, and not on the small patches of normal skin. This feature had not been observed in the other patients with this disorder or in other ichthyotic disorders. Light microscopy showed typical features of CRIE, as well as a perivascular lymphohistiocytic infiltrate in the superficial dermis. Electron microscopy and immunohistochemistry demonstrated that the lesions were strictly related to the ichthyotic skin, and that the dark color was due to melanosome accumulation in activated dendritic melanocytes. No amyloid deposits were observed. Brusasco et al. (1998) postulated an unusual postinflammatory hyperpigmentation reaction in response to a continuous inflammatory process in CRIE. The lack of pigment deposition in the keratinocytes may have resulted from a transfer defect, or the finding may have reflected hyperplastic stimulation of the epidermis.

Krunic et al. (2003) reported a 32-year-old white man with a history of red, scaly skin since birth. At age 10 years, he developed enlarging white spots on the trunk and extremities. Physical examination showed diffuse intense erythema on the face, trunk, and extremities, with fine scaling and discrete hyperkeratotic patches on the upper trunk and back. There were patches of apparently normal skin on the abdomen, upper chest, and back. On the limbs, the areas of normal unaffected skin were interspersed with erythematous scaly patches forming a reticulated pattern. Histopathologic study of the affected erythematous skin showed hyperkeratosis, a thick granular layer, acanthosis, and paranuclear vacuolization in some keratinocytes. Ultrastructural study showed binuclear cells and granular filamentous paranuclear material within the vacuolized keratinocytes.

Choate et al. (2010) summarized the clinical features of ichthyosis with confetti (IWC), a very rare, sporadic severe skin disease in which affected subjects are born with erythroderma owing to defective skin barrier function, prominent scale, and palmoplantar keratoderma. Poor skin integrity leads to bacterial infections and, frequently, impaired growth and development. Early in life, hundreds to thousands of pale confetti-like spots appear across the body surface and increase in number and size with time. Histology of ichthyotic skin shows epidermal thickening and disordered differentiation above the basal layer, with perinuclear vacuolization, lack of a granular layer, and hyperkeratosis with retained nuclei in the stratum corneum. Choate et al. (2010) studied 7 kindreds with characteristic IWC. Biopsy of confetti spots in different kindreds revealed that these have normal histology, consistent with each representing a revertant from clonal expansion of a normal stem cell.

Aarau Disease

In Aarau, Switzerland, Itin et al. (2003) described a 12-year-old girl with what they considered to be a 'new' disorder of cornification. The patient developed an ichthyosis vulgaris (146700)-like skin disorder 6 months after birth. Several years later, the clinical features changed considerably. The patient had developed streaks of hyperkeratotic, slightly scaling skin with underlying erythema distributed in a reticulate, occasionally annular pattern on the trunk and extremities. Lesions were stable and had not changed significantly in size or distribution over the ensuing years. The initial generalized skin lesions in this patient resolved, and erythrokeratodermic streaks and plaques developed, which was considered distinct from patients with CRIE. Histopathologic and ultrastructural findings were nonspecific, and there was no evidence of a metabolic disorder. Specifically, the pathognomonic features of CRIE, such as keratinocyte vacuolization, binucleate cells, and perinuclear shells, were not observed. The parents of the patient were nonconsanguineous, and no family members had this or any similar skin disorder. Itin et al. (2003) noted that the disorder in their patient shared several clinical features with CRIE (Marghescu et al., 1984), but was nonetheless distinct. Because of partial clinical overlap with erythrokeratodermia variabilis (EKV; 133200), Itin et al. (2003) screened for mutations in several connexin genes but found none. Itin et al. (2003) speculated that this disorder of cornification represented a separate new entity, which they proposed to call 'Aarau disease.'

Inheritance

In a review of CRIE, Krunic et al. (2003) noted that only a small number of patients with sporadic occurrence have been documented, suggesting new dominant mutation as a cause of the condition.

Mapping

Choate et al. (2010) compared genotypes of DNA from blood and cultured keratinocytes from biopsies of diseased and revertant skin of 1 subject. In contrast to blood and disease keratinocytes, revertant DNA showed a single large segment of copy-neutral loss of heterozygosity on chromosome 17q extending from 34.5 Mb to the telomere at 78.7 Mb. Three additional revertant spots from this subject also showed copy-neutral loss of heterozygosity extending from proximal 17q to the telomere, each with different inferred start sites for loss of heterozygosity, which excluded simple genetic mosaicism. In each revertant, the same parental haplotype was lost, consistent with loss of dominant mutation. Choate et al. (2010) then analyzed 28 revertant spots from 5 additional patients. All revertants showed copy-number loss of heterozygosity on 17q extending to the telomere. These observations confined the disease locus to an interval on 17q containing a gene cluster encoding 28 type 1 keratins and 24 keratin-associated proteins.

Molecular Genetics

Choate et al. (2010) sequenced the entire critical interval for IWC in a parent-child trio and identified a de novo mutation in the keratin-10 gene (KRT10; 148080) in the affected subject. The mutation abolished the canonical splice acceptor site of intron 6 (148080.0015) and was absent in revertant spots. Sequencing of KRT10 from genomic DNA and disease keratinocyte cDNA in the 6 other IWC kindreds identified de novo mutations in all 4 simplex kindreds and transmitted mutations in the 2 multiplex kindreds (see, e.g., 148080.0016-148080.0018). All mutations resulted in cDNAs encoding frameshifts that entered the same alternative C-terminal reading frame. Mutations included 2 additional intron 6 splice acceptor mutations, an intron 6 splice donor site mutation that results in skipping of exon 6, 2 frameshift mutations in exon 7, and an exon 6 mutation that creates a premature splice donor site. All of these mutations were absent in control chromosomes, and each was lost in revertant spots. On the basis of these findings, Choate et al. (2010) concluded that mutations in KRT10 cause ichthyosis with confetti.