A newborn presenting with congenital blistering
Authors: Klein Izabella , Bergman Reuven , Indelman Margerita , Sprecher Eli 
Published: April 2004

A baby girl was born to unrelated parents after an uneventful pregnancy. A dermatologic consultation was requested because of widespread skin blistering observed immediately after birth over most parts of the body. On examination, the baby appeared well. General physical inspection was unremarkable. Examination of the skin revealed the presence of numerous blisters and erosions scattered over the trunk, limbs, palms, and soles (Fig. 1a,b). The hair, nails, and buccal mucosa appeared normal. Routine laboratory tests were within normal limits. Although the parents did not recall any history of blistering disease in their respective families, the patient's mother, aged 29 years, mentioned the fact that she had suffered since early childhood from thickening of the palms and soles. A brother and her father displayed similar features. At the age of 20 years, she was treated with retinoids with worsening of her skin condition. Examination of the mother revealed diffuse palmoplantar keratoderma (Fig. 1c), as well as fine scaling visible over all parts of the body, except for the face. No blisters or erosions were observed. The parents did not consent to a skin biopsy from their daughter. A biopsy obtained from the mother's skin revealed orthohyperkeratosis, hypergranulosis, and marked vacuolar degeneration confined to the upper spinous and granular layers (Fig. 1d). The vacuolated keratinocytes contained irregularly shaped and enlarged keratohyaline granules. Electron microscopic examination of deparaffinized sections revealed perinuclear vacuolar changes and tonofilament clumping in the suprabasal layers of the epidermis (Fig. 1e). Taken together, these clinical and histologic findings suggested a diagnosis of epidermolytic hyperkeratosis (EHK; MIM113800), an autosomal dominant genodermatosis caused by mutations in keratin 1 (KRT1) or keratin 10 (KRT10) genes (Rothnagel JA, Dominey AM, Dempsey LD, et al. Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science 1992; 257: 1128–1130; Cheng J, Syder AJ, Yu QC, et al. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation‐specific epidermal keratin genes. Cell 1992; 70: 811–819; Chipev CC, Korge BP, Markova N, et al. A leucine–proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell 1992; 70: 821–828).

Clinical and molecular analysis of epidermolytic hyperkeratosis (EHK). (a) Blistering is especially prominent over the palms and soles of the patient. (b) Extensive blistering and erosions are observed on the buttocks of the patient. (c) The newborn's mother displays marked palmar hyperkeratosis. (d) A biopsy obtained from the mother's skin demonstrates papillomatosis, orthohyperkeratosis, hypergranulosis, and marked vacuolar changes in the keratinocytes of the upper spinous and granular layers (hematoxylin and eosin, ×100). (e) Electron microscopic examination of a skin biopsy reveals both vacuolization and tonofilament clumping within the keratinocytes of the spinous layer (×3000). (f) Mutation analysis of a DNA sample obtained from the patient uncovers a heterozygous single nucleotide TC transition (arrow) at cDNA position 482 of the keratin 1 (KRT1) gene, which is predicted to result in the substitution of a proline residue for a leucine residue at position 161 of the amino acid sequence (right panel). The wild‐type sequence is shown in the left panel

image

After having obtained written informed consent according to a protocol approved and reviewed by the local Helsinki Committee, blood samples were obtained from the newborn and her mother (other family members declined genetic analysis). Genomic DNA was extracted and screened first for mutations in the KRT1 gene, as several studies have reported an association between mutations in this gene and prominent palmoplantar keratoderma (DiGiovanna JJ, Bale SJ. Clinical heterogeneity in epidermolytic hyperkeratosis. Arch Dermatol 1994; 130: 1026–1035; Virtanen M, Gedde‐Dahl T Jr, Mork NJ, et al. Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression. Acta Derm Venereol 2001; 81: 163–170) (Fig. 1f). Genomic DNA was polymerase chain reaction (PCR)‐amplified with Taq polymerase and Q solution (Qiagen) using primer pairs described previously (Whittock NV, Eady RA, McGrath JA. Genomic organization and amplification of the human epidermal type II keratin genes K1 and K5. Biochem Biophys Res Commun 2000; 274: 149–152). Cycling conditions were as follows: 95 °C for 5 min; followed by 35 cycles at 95 °C for 30 s, 60 °C for 45 s, and 72 °C for 90 s; and a final extension step at 72 °C for 7 min. After purification with a QIAquick gel extraction kit, PCR fragments were directly sequenced using the BigDye terminator sequencing system on an ABI Prism 310 sequencer (PE Applied Biosystems). An heterozygous single nucleotide TC transition at cDNA position 482 of the KRT1 gene was identified in both the mother and her daughter. This mutation results in the substitution of a proline residue for a leucine residue at position 161 of the amino acid sequence (L161P). This mutation has previously been described as causing EHK in a North American family of English and Welsh ancestry (Chipev CC, Korge BP, Markova N, et al. A leucine–proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell 1992; 70: 821–828).