A number sign (#) is used with this entry because of evidence that an autosomal recessive localized or generalized intermediate epidermolysis bullosa simplex-4 (EBS4) is caused by homozygous or compound heterozygous mutation in the EXPH5 gene (612878) on chromosome 11q22.

Autosomal recessive localized or generalized intermediate epidermolysis bullosa simplex-4 (EBS4) is a rare disorder characterized by mild skin fragility with onset at birth or in early childhood, associated with acral blistering with hemorrhagic crusts. Skin fragility improves with age in most patients, although mottled pigmentation may later develop on the trunk and proximal limbs. Histology shows intrabasal cleavage (Malchin et al., 2016; Turcan et al., 2016; Diociaiuti et al., 2020).

For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).

McGrath et al. (2012) studied an Iraqi family in which 3 of 8 sibs born to first-cousin parents had inherited skin fragility and mutation in the EXPH5 gene. The clinical features were apparent from early childhood and consisted primarily of trauma-induced scale crusts and intermittent skin blistering that was mostly secondary to trauma, such as direct injury or adhesive tape, but occasionally appeared spontaneously. Some of the crusted areas were hemorrhagic, and were sometimes accompanied by bruising. Most lesions cleared over several weeks, leaving slightly atrophic scars and moderate postinflammatory hyperpigmentation. Examination revealed mild diffuse mottled hyper- and hypopigmentation on the trunk and proximal limbs. There was no bleeding tendency, nor neurologic abnormalities or increased incidence of infection. Hair color was normal. No clinical abnormalities were present in the parents or reported in any other relative.

Pigors et al. (2014) reported a 2-year-old German girl with mutations in the EXPH5 gene who was born with extensive skin erosions on the arms, thorax, and lower legs, covering about 20% of her body surface. The lesions healed rapidly without residual manifestations. During follow-up over the next 2 years, small trauma-induced serous blisters, recurrent erosions, and crusts were observed predominantly on the extremities. There was no evidence of scarring or pigment anomalies, and mucous membranes, nails, and hair were not affected.

Liu et al. (2014) studied a 4-year-old Caucasian boy with mutations in EXPH5 in whom skin fragility was first noticed when he began to walk. Accidental trauma to any part of his skin resulted in widespread small erosions and bleeding, most pronounced over the lower back, knees, and ankles. However, he was able to tolerate sticking plasters without harm. Eroded areas varied in size from a few millimeters to several centimeters, although most were small. The lesions healed with minimal scarring, except for occasional milia. The proband had prolonged bleeding from his erosions, and clotting studies showed a normal platelet count but slightly prolonged international normalized ratio, prothrombin time, and activated partial thromboplastin time. Bruising was not a clinical feature.

Rashidghamat et al. (2016) reported a 9-year-old Pakistani boy, born of first-cousin parents, who presented with skin fragility from birth and had mutation in EXPH5. He had scattered vesicles and bullae up to 1 to 2 cm in size on his limbs and trunk. Blistering worsened in hot weather. Individual blisters healed within 1 to 2 weeks, leaving postinflammatory hypopigmentation. His blistering tendency persisted but ameliorated with age. Hair, teeth, nails, and mucosae were normal. His 2-year-old brother had similar symptoms and signs from birth. Their father, whose parents were also first cousins, had similar skin fragility as a child that resolved completely by 10 years of age.

Malchin et al. (2016) described a 3-year-old Israeli Arab Christian girl, born of first-cousin parents, who had skin blisters at birth and mutation in EXPH5. The blisters gradually stopped appearing with age, but skin fragility persisted, manifesting as superficial erosions after minor trauma.

Turcan et al. (2016) studied a teenaged Moroccan girl, born of first-cousin parents, who had skin fragility and mutation in EXPH5. Fragility of the skin and predominantly acral blistering on mechanical trauma were first noted at age 1 year. At age 10, she began developing diffuse mottled pigmentation on her trunk, axillae, and proximal extremities that was not related to skin blistering. Skin fragility ameliorated with age, with only sporadic trauma-induced blisters on her extremities.

Diociaiuti et al. (2020) reported a 3-year-old Italian girl with mutation in the EXPH5 gene who at birth was noted to have a few erythematous macules with a central vesicle and grouped vesicles, as well as scattered erosions on the trunk and extremities. At age 3 years, she continued to develop a few trauma-induced vesicles and blisters, particularly in the summertime. The lesions healed but left depressed, atrophic, and hypopigmented scars.

Histologic Features

Using light microscopy to study a biopsy of nonlesional skin from 1 of 3 Iraqi sibs with inherited skin fragility, McGrath et al. (2012) observed mild acanthosis and hyperkeratosis and an irregular ruffled or jagged appearance at the dermal-epidermal junction. Immunofluorescence microscopy demonstrated that intensities of basement membrane zone antibody labeling in affected skin were not markedly different from those of controls, although some staining patterns differed from control skin. Low-magnification transmission electron microscopy revealed basement membrane keratinocyte disruption within the lower epidermis. Higher magnification showed aggregated intermediate filaments as well as an increased number of perinuclear vesicles and some vesicles clustered near the plasma membrane. McGrath et al. (2012) noted that collectively the clinicopathologic features were not diagnostic for any particular subtype of epidermolysis bullosa.

Pigors et al. (2014) examined a skin biopsy from a 2-year-old German girl with congenital skin fragility and mutation in the EXPH5 gene. Immunolabeling with a KRT14 (148066) antibody revealed clefting within the basal keratinocyte layer. Hematoxylin and eosin staining showed multiple macro- and microblisters at the dermal-epidermal junction, and mild hyperkeratosis. The authors stated that, in contrast to the previous report by McGrath et al. (2012), these morphologic findings allowed definite classification as autosomal recessive epidermolysis bullosa simplex (EBS).

Liu et al. (2014) performed electron microscopy of rubbed nonlesional skin from a 4-year-old Caucasian boy with skin fragility, and observed disruption of keratinocytes in the lower epidermis with cytolysis and acantholysis, keratin filament clumping, and prominent perinuclear cytoplasmic vesicles.

Rashidghamat et al. (2016) examined a shave biopsy of rubbed nonlesional skin from a 9-year-old Pakistani boy with skin fragility. Ultrastructural findings included blister formation within the lower pole of basal keratinocytes, disrupted and clumped keratin filaments, and an increased number of perinuclear cytoplasmic vesicles.

Malchin et al. (2016) performed histologic examination of a lesion from a 3-year-old Israeli Arab Christian girl with EBS, which showed subepidermal blister formation. Immunohistochemistry showed keratin (see 600194) staining at the base and roof of the blister, whereas collage IV (see 120130) staining was visible at the base of the blister only, consistent with a diagnosis of EBS.

Turcan et al. (2016) performed immunofluorescence microscopy of lesional skin from a patient with EBSB3 using antibody to KRT14 and observed a cleavage plane through the basal keratinocytes, consistent with basal EBS. Electron microscopy revealed intercellular widening with loss of desmosomes in the basal and suprabasal layers. Focally there were large accumulations of desmosomes and striking cell membrane pliability. Basal keratinocytes showed consistent abnormalities in keratin cytoarchitecture, with lateral aggregation and clumping of keratin filaments.

Diociaiuti et al. (2020) examined skin biopsies from a 3-year-old Italian girl with EBSB3 and observed tonofilament clumping in numerous basal keratinocytes. The authors noted that tonofilament clumping was typically seen in dominant severe EBS.

Using DNA from an affected sib with inherited skin fragility from a consanguineous Iraqi family, who was negative for mutation in the KRT5 (148040) and KRT14 (148066) genes, McGrath et al. (2012) performed whole-exome sequencing and identified homozygosity for a 1-bp deletion in the EXPH5 gene (612878.0001). Sanger sequencing confirmed the presence and segregation of the mutation in the pedigree, and the mutation was not found in 200 control chromosomes from mixed Iraqi, Iranian, Kuwaiti, and Omani populations. Analysis under the assumption of a fully penetrant autosomal recessive model generated a lod score of 3.157 for the cosegregation.

Pigors et al. (2014) sequenced the EXPH5 gene in a cohort of 35 patients with clinically suspected EBS who were negative for mutation in the KRT5 and KRT14 genes, and identified a 2-year-old German girl who was compound heterozygous for 1-bp deletions in EXPH5 (612878.0002 and 612878.0003). Her unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 100 German controls.

In a 4-year-old Caucasian boy with skin fragility, who was negative for mutation in known intraepidermal fragility-associated genes, Liu et al. (2014) sequenced the EXPH5 gene and identified compound heterozygosity for a 1-bp duplication (612878.0004) and a nonsense mutation (S750X; 612878.0005). His unaffected parents were each heterozygous for 1 of the mutations.

In a 9-year-old Pakistani boy with skin fragility from birth that improved with age, born of first-cousin parents, Rashidghamat et al. (2016) sequenced the EXPH5 gene and identified homozygosity for a nonsense mutation in the EXPH5 gene (L1217X; 612878.0006). His mother was heterozygous for the mutation; DNA was unavailable from his affected father, who was also born of first-cousin parents, or from his affected younger brother.

In a 3-year-old Israeli Arab Christian girl who was born with skin blistering and later had skin fragility and erosions, who was negative for mutation in the KRT5 and KRT14 genes, Malchin et al. (2016) sequenced the EXPH5 gene and identified homozygosity for a 1-bp deletion (612878.0007). Her unaffected first-cousin parents were heterozygous for the mutation, which was not found in 230 population-matched controls or in public variant databases.

In a teenaged Moroccan girl with skin fragility and blistering that ameliorated with age, Turcan et al. (2016) performed next-generation sequencing using a panel of 33 epidermolysis bullosa-associated genes and identified homozygosity for a nonsense mutation in the EXPH5 gene (S1306X; 612878.0008). Her unaffected first-cousin parents were heterozygous for the mutation, which was not found in public variant databases.

In a 3-year-old Italian girl with EBS, Diociaiuti et al. (2020) performed molecular testing using a panel for genodermatoses and identified homozygosity for a previously reported 1-bp deletion in the EXPH5 gene (612878.0001). Sanger sequencing confirmed homozygosity in the proband and heterozygosity in her unaffected consanguineous parents. The authors tabulated previously reported cases of EXPH5-associated EBS. They noted that all mutations occurred in exon 6.

Fine et al. (1989) reported a kindred in which 4 individuals had a phenotype consistent with localized EBS of the Weber-Cockayne type, but inherited in an autosomal recessive pattern. Except for scattered oral erosions in 1 patient, there was no evidence of associated extracutaneous disease. The authors noted the implications for genetic counseling. Two of the patients were sibs, and the other 2 were distant cousins. All family members were of Polish ancestry and had resided for generations in the same small rural community in Texas.