Epidermolysis Bullosa Simplex with Muscular Dystrophy

Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by separation of the epidermis from the underlying dermis, with the cleavage plane lying within the basal cell layer of the epithelium. The major clinical subtypes of EBS have a dominant inheritance and have been associated with genetic defects in specific domains of keratins K5 and K14 that result in abnormal organization of the keratin network and cell disruption. Autosomal recessive forms of EBS associated with extracutaneous manifestations, such as muscular dystrophy (EBS-MD) (MIM 226670) or pyloric atresia (EBS-PA) (MIM 612138), have been linked to genetic mutations in the gene for plectin ( PLEC ). PLEC mutations have also been found in 2 families with the rare dominant Ogna form of EBS. PLEC encodes for plectin, a versatile cytoskeletal linker protein abundantly expressed in several cell types. Plectin is associated with intermediate filaments, and various subplasma membrane–cytoskeleton and membrane-cytoskeleton junctional complexes in epithelia, muscles, and fibroblasts. Consistent with its numerous binding partners, plectin mutation results in pleiotropic phenotypes.

EBS with MD

Dermatologic Findings

Patients reported in literature with EBS-MD are usually born at term after an uneventful pregnancy ( Table 1 ). Consistent with an autosomic recessive inheritance, parents are often found to be related and are asymptomatic. At birth or soon after (15 days) the affected newborn develops blisters and erosions on the extremities, the back, and the face, which recur at the sites of mechanical trauma. Blisters are tense and can be hemorrhagic. Healing occurs without scarring but occasionally with mild residual atrophy. No congenital cutis aplasia (CCA) is present. One patient developed a few milia on the fingers. In all cases, no improvement of skin involvement has been described with time and skin fragility seems to be mild. Nail involvement is constant, with congenital onychodystrophy (pachyonychia) of the fingers and toes, although loss of nails is uncommon ( Fig. 1 ). Four patients had a focal plantar hyperkeratosis with crusted lesions. Dental anomalies such as premature tooth decay have been reported in 64% of cases. Some patients have presented from a few months of age with severe mucous membrane involvement with a hoarse cry, episodes of inspiratory stridor, recurrent and severe respiratory tract infections, and occasional bouts of severe respiratory insufficiency caused by swelling of the laryngeal mucosa. Laryngoscopic examination typically reveals blisters, erosions, and strictures of epiglottis and laryngeal mucous membranes with fusion of the arytenoid cartilages; the appearance of the infraglottic airway is normal. Oral lesions were noted in only 1 case and involved the tongue in particular, but clinical descriptions of patients are not always clear. Treatment of the laryngeal complications required a tracheotomy for 3 patients varying in age from 20 months to 3 years; for another patient, repeated balloon dilatations led to stabilization of respiratory problems. One patient also had urethral strictures in infancy and another patient had only urethral stricture without oral involvement. The presence of severe mucous lesions does not indicate an early onset of MD, but all patients with an early onset of MD have mucous involvement. No ophthalmologic findings have been reported and hair has been described as normal, although 2 patients had partial congenital alopecia of the scalp.

Table 1

Summary of clinical and molecular features of patients with EBS-MD and published plectin mutations

Patient	Sex/Age (Years)	Consanguinity	Origin	Skin Involvement					Muscle Involvement		Other	Mutations						Refs.
Patient	Sex/Age (Years)	Consanguinity	Origin	Age Onset	Mucosa	Nail	Teeth	Focal Plantar Keratodermy	Age of Onset (Years)	Evolution	Other	Mutation 1	Type	Exon	Mutation 2	Type	Exon	Refs.
P1	F/49	1	Japan	Birth	0	1	1	0	19	Artificial ventilation		Q1450X	ptc	32	Q1450X	ptc	32
P2	M/33	0	Malta	Birth	1	1	NA	0	2		Cerebral and cerebellar atrophy	R2465X	ptc	32	R2465X	ptc	32
P3	F/10	1	Italy	Neonatal	1	1	NA	0	0 at 10			(5905del2) 5854del2	ptc	32	(5905del2) 5854del2	ptc	32
P4	NA	1	Malta	Birth	0	NA	NA	0	Teens			R2465X	ptc	32	R2465X	ptc	32
P5	M/24	1	Spain	Neonatal	0	1	1	0	10	Unable to walk age 13		(5148del8) 5085del8	ptc	32	(5148del8) 5085del8	ptc	32
P6	NA	NA	NA	Neonatal	0	NA	NA	0	13 months			5309insG*	ptc	32	5309insG*	ptc	32
P7	NA	NA	NA	Neonatal	0	NA	NA	0	Teens			E1614X	ptc	32	E1614X	ptc	32
P8	NA	NA	NA	Neonatal	0	NA	NA	0	Childhood			R2421X	ptc	32	NA	ptc	NA
P9	F/46	1	Japan	Neonatal	0	1	0	0	30	Able to walk and carry out routine activity		(2719del9) 2668del9	In-frame del3aa	22	(2719del9) 2668del9	In-frame del3aa	22
P10	M/38	0	Japan	Neonatal	1	1	1	0	30	Unable to walk in mid-30s		(5866delC) 5815delC	ptc	32	(5866delC) 5815delC	ptc	32
P11	F/5.5	1	England	Birth	1	1	0	1	0 at 5,5			(5069del19) 5018del19	ptc	32	(5069del19) 5018del19	ptc	32
P12	M/40	0	NA	Neonatal	1	1	1	0	20	Considerable muscle weakness		(4416delC) 4365delC	ptc	32	(4359ins13) 4308ins13?	ptc	32
P13	M/9	1	Japan	Birth	1	1	1	0	Infancy	Major difficulties in walking at 9	Partial scarring alopecia	Q1936X	ptc	32	(Q1053X) Q1054X?	ptc	24
P14	M/33	0	Japan	Neonatal	0	1	1	0	5	Unable to walk at 22	Partial scarring alopecia	R2421X	ptc	32	(12633ins4) 12582ins4	ptc	33
P15	M/4	0	NA	Neonatal	1	1	0	0	0–4			Q1713X	ptc	32	R2351X	ptc	32
P16	F/52	0	Japan	Birth	0	1	1	0	25	Unable to walk age 46		R2319X	ptc	32	R2319X	ptc	32
P17	F/3	1	Lebanon	Birth	1	1	0	0	0–3			(5588insG) 5258inG	ptc	32	(5588insG) 5258inG	ptc	32
P18	M/NA		Germany	NA	0	NA	NA	0	NA			E1914X*	ptc	32	E1914X*	ptc	32
P19	F/5 months		France	Neonatal	1		NA	1	0–5 months			(2745-9 del21) 2769del21	In-frame del7aa	22	(5083delG) 5032delG	ptc	32
P20	F/29	1	Italy	Birth	0	1	0	1	Childhood			Q1910X	ptc	32	Q1910X	ptc	32
P21	NA	NA	NA	Birth	0	NA	NA	0	1			(5907ins8) 5854ins?	ptc	32	(5907ins8) 5854ins8?	ptc	32
P22	M/6 months		Spain	Birth	0	1	0	0	0–6 months		Extensive cleft lift and palate	E2005X	ptc	32	K4460X	ptc	33
P23	M/4		White	Birth	0	1	0	0	0–6 years			1287ins3*/ 957ins3	In-frame ins1aa	9	Q1518X	pct	31
P24	F/25		White	Birth	0	1	0	0	11 years	Facial weakness, ptosis, exophthalmia, dysphonia, weakness, and atrophy of trunk and limbs	Mental retardation, bilateral cataract, cardiac hypertrophy, MAV left leg, cerebral atrophy	(13803ins16) 13474ins16?	pct	33	(13803ins16) 13474ins16?	pct	33
P25	NA	NA	NA	NA	NA	NA	NA		42 years			1541ins36*	In-frame ins12aa	14	(677del9) 2637del9?	In-frame del3aa	22