Acta Dermato-Venereologica 99-13CompleteContent | Page 33
SHORT COMMUNICATION
1309
Novel PLEC Variant Causes Mild Skin Fragility, Pyloric Atresia, Muscular Dystrophy and Urological
Manifestations
Manthoula VALARI 1 , Martha THEODORAKI 2 , Ierotheos LOUKAS 3 , Sylvia GKANTSEVA-PATSOURA 2 , Georgia KARAVANA 2 ,
Vasiliki FALAINA 2 , Lilia LYKOPOULOU 1 , Roser PONS 4 , Ioannis ATHANASIOU 5 , Katarzyna WERTHEIM-TYSAROWSKA 6 , Christina
KANAKA-GANTENBEIN 1 and Dimitra KIRITSI 5 *
1
First Department of Pediatrics, Medical School and 4 First Department of Pediatrics, Neurology unit, Medical School, National and Kapodistrian
University of Athens, “Agia Sofia Childrens Hospital”, Athens, Greece, 2 Neonatal Intensive Care Unit and 3 Department of Pediatric Surgery,
General Hospital of Nikaia “Agios Panteleimon”, Peiraius, Greece, 5 Department of Dermatology, Faculty of Medicine, Medical Center, University
of Freiburg, Hauptstr. 7, DE-79104 Freiburg, and 6 Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. *E-mail:
[email protected]
Accepted Sep 12, 2019; E-published Sep 12, 2019
Epidermolysis bullosa (EB) is a clinically and genetically
relatively heterogeneous group of inherited blistering dis-
orders. The most common subtype is EB simplex (EBS),
which is usually associated with mutations in the KRT5,
KRT14, DST, EXPH5 and PLEC genes (1). Approximately
8% of patients with EBS are estimated to carry PLEC mu-
tations (2). The PLEC gene encodes the large cytolinker
protein plectin (3–5). Plectin mutations, inherited in an
autosomal recessive pattern, result in distinct phenotypes,
including EBS with muscular dystrophy (MD), EBS with
pyloric atresia (PA) and EBS with skin lesions only (3, 6).
The dominantly inherited EBS-Ogna has a mild course
restricted to skin involvement (7).
Phenotype–genotype correlations have suggested that
EBS-MD is mostly due to genetic variants in the central
rod domain of plectin and EBS-PA due to mutations outside
this domain (3, 8). Urinary tract involvement has only very
rarely been reported in patients with either EBS-PA or EBS-
MD (3, 4). To our knowledge only one case of EBS with
both PA and MD, due to compound heterozygous PLEC
mutations located in exon 32, has been reported (9). That
patient had severe skin involvement and died 3 months after
birth. We report here a patient with non-lethal EBS with
rather mild skin involvement, congenital PA, progressive
MD and mild bilateral hydronephrosis, who is compound
heterozygous for 2 PLEC genetic variants in exon 32, one
of them not having been reported previously. Thus, we
extend the phenotypic spectrum of genetic PLEC variants.
CASE REPORT
On the second day of life, an infant boy was observed to have
non-bilious vomiting with blood, without abdominal distention.
He had been born at 38 weeks’ gestation, with a weight of 2,400
g. Abdominal X-ray showed a large gastric air bubble with no gas
distally (Fig. 1A). An upper gastrointestinal tract examination with
contrast material revealed a dilated stomach with obstruction at the
pylorus, consistent with PA. Tense, and often haemorrhagic, blisters
and erosions on the trunk and extremities appeared and recurred at
sites of mechanical trauma (Fig. 1A). Similar bullous lesions were
noted in the oral mucosa. Creatine kinase (CK) was found 1,468 U/l
(normal range < 350 U/l) on the 5 th day of life. On the 6 th day of life,
laparotomy revealed PA type 2 (pyloric canal replaced by a solid cord
of tissue) and gastroduodenostomy was performed. Feeding was
started approximately 1 week after surgery, was well tolerated, and
hence gradually increased to full enteral nutrition. A renal ultrasound
at day 8 showed mild hydronephrosis. Skin lesions continued to
recur, and healing occurred without scarring, accompanied by mild
atrophy. A skin biopsy was taken for immunofluorescence mapping,
using a panel of antibodies to components of the dermo–epidermal
junction and showed intraepidermal blisters and strongly reduced
staining with 2 antibodies against plectin (Fig. 1B, 2 left
panels). All other markers stained similarly to control
skin. These findings were consistent with the diagnosis
of EBS due to PLEC mutations. A custom-designed
panel of EB-related genes was analysed by the Depart-
ment of Medical Genetics in Warsaw, Poland, using
Fig. 1. Clinical picture of the patient and diagnostics
compatible with the diagnosis of epidermolysis bullosa
simpelx due to PLEC mutations. (a) Abdominal X-ray after
birth showed a large gastric air bubble with no gas distally. Small
blisters and erosions were present over the whole integument.
(b) Immunofluorescence mapping reveals intraepidermal blisters
(white stars in plectin, integrin β4 (clone 3Ε1) and cytokeratin 5
(clone D5/16 B4) staining) and strongly reduced plectin expression
with 2 different antibodies, whereas integrin a6 shows a staining
pattern comparable to control skin. Scale: 100 μm. Immunoblot
with the 2 plectin antibodies (31 recognizing the C-terminus and
10F6 for the rod domain) reveals residual presence of full-length
plectin in lysates from patient keratinocytes, although a slightly
shorter fragment cannot be fully excluded. Plectin expression
appears to be comparably strongly reduced, regardless of the
epitope recognized by the 2 plectin antibodies. (c) At the age
of 2 years the skin phenotype has improved with mostly acral
blisters and thickened dystrophic nails.
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2019 Acta Dermato-Venereologica.
doi: 10.2340/00015555-3317
Acta Derm Venereol 2019; 99: 1309–1310