Epidermolysis bullosa simplex, localized or generalized intermediate, with mutation in EXPH5 Q82.8

Fine et al (1989) reported a family in which 4 individuals had a phenotype consistent with localized Weber-Cockayne-type EBS but inherited in an autosomal recessive manner. Apart from isolated oral erosions in one patient, there was no evidence of associated extracutaneous disease

Autosomal recessive monogenic epidermolysis bullosa simplex-1D (EBS4) with basal cleft formation, which occurs at birth or during the 1st year of life and is usually mild, is associated with a mutation in the EXPH5 gene (612878) on chromosome 11q22.3. EBS4 is a very rare (only a few families have been described to date) skin disorder characterized by traumatic blistering that increases with heat. Healing occurred with mildly atrophic, occasionally hyerpigmented but also hypopigmented scars. The severity varies. In some patients, the disease occurs localized with preferential involvement of the hands and feet. In other affected individuals, blistering may also occur on the trunk. In a few patients, diffusely distributed mottled pigmentation occurred independently of blisters. In most patients, the condition improves with age.

No evidence of mutations in KRT5 and KRT14 genes; duplications, depletions, and nonsense mutations in EXPH5.

In the Iraqi family studied by McGrath et al. (2012), clinical features appeared in early childhood and consisted primarily of trauma-induced blisters and planar (sometimes hemorrhagic) crusts of the skin. Healing within a few weeks with mild atrophic scars and minor postinflammatory hyperpigmentation.

Mild diffuse mottled hyper- and hypopigmentation on the trunk and proximal limbs was notable. No mucosal involvement.

Pigors et al (2014) reported on a two-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 approximately 20% of the body surface. The lesions healed without residuals. No mucosal involvement. Nails and hair were not affected.

In the 4-year-old Caucasian boy with mutations in EXPH5 (Liu et al. 2014), traumatic blistering began at walking age. Lower back, knees, and ankles were affected.

The size of the blisters varied from a few millimeters to several centimeters. Only discrete scarring. Very isolated milia.

Traumatic blistering of the extremities and trunk was observed in a 9-year-old Pakistani boy shortly after birth (Rashidghamat et al. 2016). The size of the blisters varied from 1 to 2 cm. Blister formation worsened during hot weather. The individual blisters healed within 1 to 2 weeks, leaving postinflammatory hypopigmentation. However, the tendency to blister decreased with age. Hair, teeth, nails, and mucous membranes were normal.

Other analogous findings were reported by Malchin et al. (2016) and Diociaiuti et al. (2020).

The Moroccan girl described by Turcan et al. (2016) developed diffuse mottled pigmentation on the trunk, axillae, and proximal extremities at age 10 years that was not related to blistering of the skin. Skin fragility decreased with age, and only sporadic trauma-induced blisters occurred on the extremities.

Histology shows intrabasal cleavage (Malchin et al.2016; Turcan et al. 2016; Diociaiuti et al. 2020).

1. Diociaiuti A et al. (2020) Autosomal recessive epidermolysis bullosa simplex due to EXPH5 mutation: neonatal diagnosis of the first Italian case and literature review. J. Europ. Acad. Derm. Venereol. 34: e694-e697.
2. Fine JD et al. (1989) Epidermolysis bullosa simplex: identification of a kindred with autosomal recessive transmission of the Weber-Cockayne variety. Pediat. Derm 6: 1-5.
3. LiuL et al. (201) Mutations in EXPH5 result in autosomal recessive inherited skin fragility. Brit J Derm 170: 196-199.
4. Malchin N et al (2016) A novel homozygous deletion in EXPH5 causes a skin fragility phenotype. Clin Exp Derm 41: 915-918.
5. McGrath JA et al (2012) Germline mutation in EXPH5 implicates the Rab27B effector protein Slac2-b in inherited skin fragility. Am J Hum Genet 91: 1115-1121.
6. Pigors M et al (2014) Molecular heterogeneity of epidermolysis bullosa simplex: contribution of EXPH5 mutations. J Invest Derm 134: 842-845.
7. Rashidghamat E et al (2016) Mutations in EXPH5 underlie a rare subtype of autosomal recessive epidermolysis bullosa simplex. Brit J Derm 174: 452-453.
8. Turcan I et al (2016) Association of epidermolysis bullosa simplex with mottled pigmentation and EXPH5 mutations. JAMA Derm 152: 1137-1141.