ORPHA: 89838;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.13 | Epidermolysis bullosa simplex 2D, generalized, intermediate or severe, autosomal recessive | 619599 | Autosomal recessive | 3 | KRT5 | 148040 |
A number sign (#) is used with this entry because autosomal recessive generalized intermediate or severe epidermolysis bullosa simplex 2D (EBS2D) is caused by homozygous mutation in the KRT5 gene (148040) on chromosome 12q13.
Autosomal recessive generalized intermediate or severe epidermolysis bullosa simplex 2D (EBS2D) is characterized by widespread intraepidermal skin blistering and erosions from birth (summary by Vahidnezhad et al., 2019).
For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).
Tryon et al. (2019) studied a 2-year-old boy from a consanguineous Middle Eastern family who presented at birth with blistering and sloughing of his 'nearly transparent' skin. At the time of evaluation, 90% of his body surface area was affected by blisters, crusts, erosions, and hyperpigmentation. Oral blistering and lesions were common, and teeth were slow to erupt. Fingernails were intact, but pseudosyndactyly had developed on hands and feet. He reportedly experienced recurrent upper respiratory tract infections. He had some extracutaneous features including developmental delays, hearing loss, pectus carinatum, and growth retardation. He died at age 26 months of age of septic shock. The parents and older brother were unaffected.
Vahidnezhad et al. (2019) described 2 patients with EBS and homozygous mutations in the KRT5 gene. Patient 2 was a 4-year-old boy born of first-cousin Syrian parents who had generalized skin blistering from birth with occasional involvement of oral mucous membranes. Bullae were observed mainly on the soles and abdomen and healed without scarring. The parents and older brother were unaffected. Patient 3 was a girl born of first-cousin Syrian parents who at birth had extensive skin defects and multiple blisters on feet, legs, hands, and right arm. Her leg and feet were underdeveloped, and skin was atrophic. A few hours after birth more blisters developed on her trunk, face, and mouth, and eventually about 80% of the body was affected. She died at 4 weeks of age. The mother's sister had been born with similar skin manifestations and died shortly after birth.
The transmission pattern of EBS2D in the families reported by Tryon et al. (2019) and Vahidnezhad et al. (2019) was consistent with autosomal recessive inheritance.
In a 2-year-old boy with severe EBS, Tryon et al. (2019) detected homozygosity for a 1-bp deletion in the KRT5 gene (148040.0022) that resulted in premature truncation of the protein in the 1B domain. The unaffected parents and brother were heterozygous for the mutation. Immunofluorescence staining of a full-thickness skin biopsy from the patient showed normal staining for collagens VII (see 120120) and XVII (113811) and laminins A3 (600805), B3 (150310), and C2 (150292). However, the epidermis was thin, with discontinuous sparse staining for keratin-5 and -14 (148066). Immunoelectron microscopy showed disorganization of cytoplasmic contents of basal keratinocytes and mostly absent intermediate filaments.
In 2 patients from consanguineous families with autosomal recessive generalized EBS, Vahidnezhad et al. (2019) identified mutations in the KTY5 gene. Patient 2 was homozygous for a c.472G-A transition that resulted in an asp158-to-asn substitution (D158N; 148040.0023). Patient 3 was homozygous for a c.1440-1G-A transition at the acceptor splice site of intron 7 (148040.0024). Immunofluorescence staining of patient skin showed complete absence of keratin-5. The unaffected parents of each patient were heterozygous for the respective mutations.
Tryon, R. K., Tolar, J., Preusser, S. M., Riddle, M. J., Keene, D. R., Bower, M., Thyagarajan, B., Ebens, C. L. A homozygous frameshift variant in the KRT5 gene is compatible with life and results in severe recessive epidermolysis bullosa simplex. JAAD Case Rep. 5: 576-579, 2019. [PubMed: 31312705] [Full Text: https://doi.org/10.1016/j.jdcr.2019.03.025]
Vahidnezhad, H., Youssefian, L., Daneshpazhooh, M., Mahmoudi, H., Kariminejad, A., Fischer, J., Christiansen, J., Schneider, H., Guy, A., Liu, L., McGrath, J. A., Has, C., Uitto, J. Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 'knock-out'. Matrix Biol. 83: 48-59, 2019. [PubMed: 31302245] [Full Text: https://doi.org/10.1016/j.matbio.2019.07.002]