Ectodermal Dysplasia/skin Fragility Syndrome

Watchlist

(log in to enable)

Retrieved

2019-09-22

Source

Omim

Trials

—

Genes

PKP1, DSP

Drugs

Allantoin, Allogeneic adipose-derived adult mesenchymal stem cells contained in a fibrin-based bioengineered dermis, Allogeneic human dermal fibroblasts

Allantoin, Allogeneic adipose-derived adult mesenchymal stem cells contained in a fibrin-based bioengineered dermis, Allogeneic human dermal fibroblasts, Allogeneic skin-derived ABCB5-positive mesenchymal stem cells, Bilayer engineered skin composed of keratinocytes (patient autologous) and fibroblasts (donor allogeneic) in a plasma matrix, Diacerein, Dry extract from Betulae cortex (birch bark), Human dermal fibroblasts cultured on a bioresorbable polyglactin mesh, Losartan

Interested in hearing about new therapies?

A number sign (#) is used with this entry because of evidence that ectodermal dysplasia/skin fragility syndrome is caused by homozygous or compound heterozygous mutation in the plakophilin-1 gene (PKP1; 601975) on chromosome 1q32.

Clinical Features

McGrath et al. (1997, 1999) described a boy with a unique skin disorder comprising trauma-induced skin fragility and congenital ectodermal dysplasia affecting hair, nails, and sweat glands. The proband reported by McGrath et al. (1997) was a 6-year-old boy with unrelated parents. There was no family history of skin blistering or other significant abnormalities. At birth, all of his skin was lobster pink, with blistering on the soles. Over the first 48 hours, he developed more severe blistering and desquamation on his face, limbs, and buttocks. His hair was noted to be short and sparse, and his nails were thickened and dystrophic. Subsequently, his skin continued to show fragility, with trauma-induced tearing and blisters on the pressure points of the soles after prolonged standing or walking. Light microscopy of the skin revealed thickening of the epidermis and extensive widening of keratinocyte intercellular spaces, extending from the first suprabasal layer upward. Electron microscopy showed a loss of keratinocyte-keratinocyte adhesion, and desmosomes, particularly in the lower suprabasal layers, were small and reduced in number. There was complete absence of immunostaining for plakophilin-1 in the skin. The proband was found to be a compound heterozygote for a premature termination codon on each of the 2 alleles of the PKP1 gene (see 601975.0001 and 601975.0002).

McGrath (2000) reported observations on 2 further unrelated cases of this syndrome. In one of these patients, a 17 year old, the scalp hair started to regrow a little after the age of 7 years, and the abnormality of sweating became much less marked. Most notable, however, was the painful, disabling cracking and hyperkeratosis of the palms and soles, also seen in the 3 other cases. The affected toddlers and children had to be carried about by their parents, and the 17-year-old patient, who had normal intelligence like the others, had gone through school in a wheelchair due to the effects of the disease on the soles of the feet. All 4 patients, who were from different families, showed loss of plakophilin-1.

Using immunohistochemistry and quantitative electron microscopy, McMillan et al. (2003) examined suprabasal desmosomes from 3 PKP1-deficient patients, an unaffected carrier with a PKP1-heterozygous acceptor splice site mutation, and 5 healthy control subjects. Compared with those in controls, desmosomes in PKP1-null patients were reduced dramatically both in size (49%) and frequency (61%) in the lower suprabasal layers (p less than 0.01). In the lower suprabasal compartment of the heterozygous carrier, corresponding reductions were 37% and 20%, respectively (p less than 0.01). Surprisingly, in the PKP1-null patients' upper suprabasal layer, desmosome size was larger (59%, p less than 0.01) than the control value, and showed increased desmoglein-1 (125670) and PKP2 (602861) staining. The upper suprabasal layer desmosome frequency in PKP1-null patients was similar to that seen in the lower suprabasal compartment but reduced by 43% compared to controls. The carrier showed no difference in the upper suprabasal layer desmosome size and frequency compared with the controls (p greater than 0.05). The PKP1-null patients showed poorly developed inner and outer desmosomal plaques. Thus, both the patients and unaffected carrier showed reductions in the lower suprabasal layer desmosome size and number, despite only PKP1-null patients exhibiting any phenotype. These findings attest to the molecular recruiting and stabilizing roles of PKP1 in desmosome formation, particularly in the lower suprabasal compartment.

Molecular Genetics

In a patient with ectodermal dysplasia/skin fragility syndrome, McGrath et al. (1997) identified compound heterozygosity for premature termination codons in the PKP1 gene (601975.0001-601975.0002).

In a 17-year-old patient with ectodermal dysplasia/skin fragility syndrome, Whittock et al. (2000) identified a homozygous splice site mutation in the PKP1 gene (601975.0003).